Aminotetralin-derived urea modulators of vanilloid VR1 receptor

ABSTRACT

This invention is directed to vanilloid receptor VR1 ligands. More particularly, this invention relates to β-aminotetralin-derived ureas that are potent antagonists or agonists of VR1 which are useful for the treatment and prevention of inflammatory and other pain conditions in mammals.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This applicaiton claims priority to U.S. Provisional ApplicationNo. 60/381,575, filed May 17, 2003.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] The research and development of the invention described below wasnot federally sponsored.

BACKGROUND OF THE INVENTION

[0003] This invention is directed to novel vanilloid receptor VR1ligands. More particularly, this invention relates to novelβ-aminotetralin-derived ureas that are potent antagonists or agonists ofVR1 and exhibit activity in animal models of hyperalgesia and colitis,and are useful for the treatment and prevention of pain conditions inhumans including arthritis, and for the treatment of irritable-bowelsyndrome and associated conditions.

[0004] Noxious chemical, thermal and mechanical stimuli exciteperipheral nerve endings of small diameter sensory neurons (nociceptors)in sensory ganglia (e.g., dorsal root, nodose and trigeminal ganglia)and initiate signals that are perceived as pain. These neurons arecrucial for the detection of harmful or potentially harmful stimuli(heat) and tissue damage (local tissue acidosis and/or stretch) thatarise from changes in the extracellular space during inflammatory orischaemic conditions (Wall, P. D., and Meizack, R., Textbook of Pain,1994, New York: Churchill Livingstone). Nociceptors transduce noxiousstimuli into membrane depolarization that triggers action potential,conducts the action potential from the sensory sites to the synapses inthe CNS, and conversion of action potentials invokes a perception ofpain, discomfort, and appropriate mechanical/physical protectivereflexes. At the molecular level, nociception is carried out by ionchannels or receptors. Plant derived vanilloid compounds (capsaicin andits ultrapotent analog, resiniferatoxin, etc.) are known to selectivelydepolarize nociceptors and elicit sensations of burning pain—thesensation that is typically obtained by hot chili peppers. Therefore,capsaicin mimics the action of physiological/endogenous stimuli thatactivates the “nociceptive pathway”. Recent advances in pain biologyhave identified receptors for vanilloids, protons (i.e., acidicsolutions), and for heat. Because nociceptors are involved with unwantedpain and inflammatory conditions in human beings and animals, modulationof their nociceptive pathway is important in palliative and othertherapies.

[0005] Walpole and colleagues at Sandoz reported on the firstcompetitive antagonist of the sensory neuron excitants capsaicin andresineriferatoxin (Walpole, C. S. J. et. al., J. Med. Chem. 1994, 37,1942). Subsequently, capsazepine has been shown to be a vanilloidreceptor antagonist. Capsazepine, however, is not aminotetralin-derived.Jee Woo Lee and colleagues at Pacific Corporation disclosed thiocarbamicacid derived VR1 antagonists in WO0216317A1 and vanilloid receptormodulators in WO0216318A1 and WO0216319A1 but these applications do notdisclose or describe α-substituted β-aminotetralins. Hutchinson andcolleagues at Neurogen describe a diaryl piperazinyl ureas and relatedcompounds as capsaicin receptor ligands in WO02082212A1 butaminotetralins are not covered. Scientists at the Universidad MiguelHernandez in Alicante, the Universidad de Valencia and the ConsejoSuperior de Investigaciones Cientificas (CSIC) in Barcelona have used acombinatorial chemistry-based approach to discover compounds thatmodulate the vanilloid VR1 receptor and have disclosed twotrialkylglycine-based compounds as noncompetitive VR1 channel blockers(Garcia-Martinez, C. et al. Proc Natl Acad Sci USA 2002, 99(4): 2374)but none are aminotetralin-derived.

[0006] U.S. Pat. Nos. 6,140,354 and 6,201,025 by Dax et. al. teach thesynthesis of N-acylated and N-alkylated α-substituted β-aminotetralinsbut do not describe the synthesis of ureido β-aminotetralins. U.S. Pat.No. 6,169,116 B1 by Swoboda describes β-aminotetralins and theirpharmaceutical uses but does not describe the synthesis of α-substitutedβ-aminotetralins and does not describe the synthesis of ureidoβ-aminotetralins. European patent application 0064964 by Arvidssonteaches the synthesis of N-alkylated α-alkyl-β-aminotetralins in whichthe alkyl substituent in the α-position is hydrogen or C₁₋₆alkyl butdoes not describe the synthesis of β-aminotetralins substituted withgroups other than hydrogen or C₁₋₆alkyl in α-position nor describe thesynthesis of ureido β-aminotetralins.

[0007] Thus, there is a need for potent modulators of VR, and inparticular, for novel β-aminotetralin-derived ureas that exhibit potentbinding affinity for the human and rat VR1 ion channel. There is also aneed for novel β-amino-tetralin-derived ureas that act as potentfunctional antagonists and/or agonists of the human and rat VR1 ionchannel. Finally, there is a need for novel β-aminotetralin-derivedureas that bind with high affinity to VR1 and also act as potentfunctional antagonists of the human and rat VR1 ion channel.

SUMMARY OF THE INVENTION

[0008] The present invention is directed to compositions comprising acompound of Formula (I):

[0009] wherein:

[0010] R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₁₋₈alkanyloxy optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl;C₁₋₈alkanylthio optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy;nitro; amino; C₁₋₈alkanylamino; C₁₋₈dialkanylamino;C₃₋₈cycloalkanylamino; cyano; carboxy; C₁₋₇alkanyloxycarbonyl;C₁₋₇alkanylcarbonyloxy; formyl; phenyl optionally substituted with oneto three substituents independently selected from the group consistingof halogen, hydroxyl, nitro, amino and cyano; aroyl; carbamoyl; amidino;(C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl;

[0011] n is an integer from 1 to 3;

[0012] m is an integer from 0 to 3;

[0013] R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₂₋₈alkenyl;C₁₋₈alkylidenyl; C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl;phenyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, fluorinatedalkanyl, cyano, nitro, amino, C₁₋₈alkanylamino, and C₁₋₈dialkanylamino;naphthyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, fluorinatedalkanyl, cyano, nitro, amino, C₁₋₈alkanylamino, and C₁₋₈dialkanylamino;phenoxy optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinated alkanyl, cyano and nitro; andheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₆alkanyl andhalogen wherein said heteroaryl is pyridyl, pyrimidyl, furyl, thienyl orimidazolyl; pyrrolidino; and piperidino;

[0014] L is a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl,or C₃₋₈cycloalkandiyl;

[0015] R₃ is selected from the group consisting of phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; naphthyl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl,nitro, amino, di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; andheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₈alkanyl,halogen, nitro, amino and cyano wherein said heteroaryl is quinolinyl,quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;

[0016] R₄ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0017] R₅ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0018] X is selected from the group consisting of O and S; and

[0019] enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.

[0020] Preferred embodiments of the present invention are those inwhich: (1) R₁ is a substituent independently selected from the groupconsisting of hydrogen, hydroxy, fluoro, chloro, bromo, andC₁₋₈alkanyloxy; (2) R₁ is a substituent independently selected from thegroup consisting of fluoro, chloro, bromo, C₁₋₈alkanyloxy, (3) R₂ isindependently selected from the group consisting of hydrogen,C₂₋₈alkenyl, C₂₋₈alkenyl, C₁₋₈alkylidenyl, C₁₋₈alkylidynyl,C₃₋₈cycloalkanyl, phenyl (optionally substituted with one to threesubstituents independently selected from the group consisting of fluoro,chloro, bromo, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, and fluorinated alkanyl), naphthyl (optionallysubstituted with one to three substituents independently selected fromthe group consisting of fluoro, chloro, bromo, hydroxy, C₁₋₈alkanyl,C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, and fluorinated alkanyl), and aheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₆alkanyl andhalogen wherein the heteroaryl is pyridyl, pyrimidyl, furyl, thienyl orimidazolyl; (4) L is a direct bond or C₁₋₈alkanylene; and (5) R₃ isselected from the group consisting of naphthyl substituted withhydroxyl; quinolinyl optionally substituted with one or moresubstituents selected from the group consisting of methyl and chloro,quinolinyl-N-oxide, isoquinolinyl optionally substituted with one ormore substituents selected from the group consisting of methyl andchloro and isoquinolinyl-N-oxide.

[0021] Finally, the present invention is directed to pharamceuticalcompositions containing compounds of Formula (I), as well as to methodsof treatment of diseases and conditions by administration of thesecompositions, and also to pharmaceutical kits containing them.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022]FIG. 1 shows the IC₅₀ values of the competitive vanilloidantagonist capsazepine for inhibition of calcium flux induced by anumber of different stimuli known to activate VR1.

[0023]FIG. 2 shows the IC₅₀ values for inhibition by a compound of theinvention of the calcium flux induced by a number of different stimuliknown to activate VR1.

[0024]FIG. 3 shows inhibition by a compound of the invention ofcapsaicin-induced contraction of guinea pig bronchial rings in anisolated tissue assay.

[0025]FIG. 4 shows inhibition by another compound of the invention ofcapsaicin-induced contraction of guinea pig bronchial rings in anisolated tissue assay.

DETAILED DESCRIPTION OF THE INVENTION

[0026] As used herein, the following underlined terms are intended tohave the following meanings:

[0027] “C_(a-b)” (where a and b are integers) refers to a radicalcontaining from a to b carbon atoms inclusive. For example, C₁₋₃ denotesa radical containing 1, 2 or 3 carbon atoms.

[0028] “Fluorinated alkyl” refers to a saturated branched or straightchain hydrocarbon radical derived by removal of 1 hydrogen atom from theparent alkane; the parent alkane contains from 1 to 6 carbon atoms with1 or more hydrogen atoms substituted with fluorine atoms up to andincluding substitution of all hydrogen atoms with fluorine. Preferredfluorinated alkyls include trifluoromethyl substituted alkyls andperfluorinated alkyls; more preferred fluorinated alkyls includetrifluoromethyl, perfluoroethyl, 2,2,2-trifluoroethyl, perfluoropropyl,3,3,3-trifluoroprop-1-yl, 3,3,3-trifluoroprop-2-yl,1,1,1,3,3,3-hexafluoroprop-2-yl; a particularly preferred fluorinatedalkyl is trifluoromethyl.

[0029] “Fluorinated alkanyloxy” refers to a radical derived from afluorinated alkyl radical attached to an oxygen atom with the oxygenatom having one open valence for attachment to a parent structure.

[0030] “Alkyl:” refers to a saturated or unsaturated, branched,straight-chain or cyclic monovalent hydrocarbon radical derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkane, alkene or alkyne. Typical alkyl groups include, but are notlimited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propylssuch as propan-1-yl, propan-2-yl , cyclopropan-1-yl, prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl, cycloprop-1-en-1-yl;cycloprop-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls suchas butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl,cyclobutan-1-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Wherespecific levels of saturation are intended, the nomenclature “alkanyl”,“alkenyl” and/or “alkynyl” is used, as defined below. In preferredembodiments, the alkyl groups are (C₁₋₈) alkyl, with (C₁₋₃) beingparticularly preferred.

[0031] “Alkanyl:” refers to a saturated branched, straight-chain orcyclic monovalent hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent alkane. Typicalalkanyl groups include, but are not limited to, methanyl; ethanyl;propanyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, etc.;butyanyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl,2-methyl-propan-2-yl, cyclobutan-1-yl, etc.; and the like. In preferredembodiments, the alkanyl groups are (C₁₋₈) alkanyl, with (C₁₋₃) beingparticularly preferred.

[0032] “Alkenyl:” refers to an unsaturated branched, straight-chain orcyclic monovalent hydrocarbon radical having at least one carbon-carbondouble bond derived by the removal of one hydrogen atom from a singlecarbon atom of a parent alkene. The radical may be in either the cis ortrans conformation about the double bond(s). Typical alkenyl groupsinclude, but are not limited to, ethenyl; propenyls such asprop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl,cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such asbut-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.;and the like. In preferred embodiments, the alkenyl group is (C₂₋₈)alkenyl, with (C₂₋₃) being particularly preferred.

[0033] “Alkenyl:” refers to an unsaturated branched, straight-chain orcyclic monovalent hydrocarbon radical having at least one carbon-carbontriple bond derived by the removal of one hydrogen atom from a singlecarbon atom of a parent alkyne. Typical alkynyl groups include, but arenot limited to, ethynyl; propynyls such as prop-1-yn-1-yl,prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl,but-3-yn-1-yl, etc.; and the like. In preferred embodiments, the alkynylgroup is (C₂₋₈) alkynyl, with (C₂₋₃) being particularly preferred.

[0034] “Alkyldiyl:” refers to a saturated or unsaturated, branched,straight-chain or cyclic divalent hydrocarbon radical derived by theremoval of one hydrogen atom from each of two different carbon atoms ofa parent alkane, alkene or alkyne, or by the removal of two hydrogenatoms from a single carbon atom of a parent alkane, alkene or alkyne.The two monovalent radical centers can form bonds with the same ordifferent atoms. Typical alkyldiyls include, but are not limited tomethandiyl; ethyldiyls such as ethan-1,1-diyl, ethan-1,2-diyl,ethen-1,1-diyl, ethen-1,2-diyl; propyldiyls such as propan-1,1-diyl,propan-1,2-diyl, propan-2,2-diyl, propan-1,3-diyl, cyclopropan-1,1-diyl,cyclopropan-1,2-diyl, prop-1-en-1,1-diyl, prop-1-en-1,2-diyl,prop-2-en-1,2-diyl, prop-1-en-1,3-diyl, cycloprop-1-en-1,2-diyl,cycloprop-2-en-1,2-diyl, cycloprop-2-en-1,1-diyl, prop-1-yn-1,3-diyl,etc.; butyldiyls such as, butan-1,1-diyl, butan-1,2-diyl,butan-1,3-diyl, butan-1,4-diyl, butan-2,2-diyl,2-methyl-propan-1,1-diyl, 2-methyl-propan-1,2-diyl, cyclobutan-1,1-diyl;cyclobutan-1,2-diyl, cyclobutan-1,3-diyl, but-1-en-1,1-diyl,but-1-en-1,2-diyl, but-1-en-1,3-diyl, but-1-en-1,4-diyl,2-methyl-prop-1-en-1,1-diyl, 2-methylprop-2-en-1,1-diyl,buta-1,3-dien-1,1-diyl, buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl,buta-1,3-dien-1,4-diyl, cyclobut-1-en-1,2-diyl, cyclobut-1-en-1,3-diyl,cyclobut-2-en-1,2-diyl, cyclobuta-1,3-dien-1,2-diyl,cyclobuta-1,3-dien-1,3-diyl, but-1-yn-1,3-diyl, but-1-yn-1,4-diyl,buta-1,3-diyn-1,4-diyl, etc.; and the like. Where specific levels ofsaturation are intended, the nomenclature alkandiyl, alkendiyl and/oralkyndiyl is used. In preferred embodiments, the alkyldiyl group is(C₁₋₈) alkyldiyl, with (C₁₋₈) being particularly preferred. Alsopreferred are saturated acyclic alkandiyl radicals in which the radicalcenters are at the terminal carbons, e.g., methandiyl; ethan-1,2-diyl;propan-1,3-diyl; butan-1,4-diyl; and the like (also referred to asalkylenos, as defined infra).

[0035] “Vic Alkyldiyl:” refers to a saturated or unsaturated, branched,straight-chain or cyclic hydrocarbon radical having two adjacentmonovalent radical centers derived by the removal of one hydrogen atomfrom each of two adjacent carbon atoms of a parent alkane, alkene oralkyne. The two monovalent radical centers can form bonds with the sameor different atom(s). Typical vic alkyldiyls include, but are notlimited to vic ethyldiyls such as ethan-1,2-diyl, ethen-1,2-diyl; vicpropyldiyls such as propan-1,2-diyl, cyclopropan-1,2-diyl,prop-1-en-1,2-diyl, prop-2-en-1,2-diyl, cycloprop-1-en-1,2-diyl, etc.;vic butyldiyls such as butan-1,2-diyl, 2-methyl-propan-1,2-diyl,cyclobutan-1,2-diyl, but-1-en-1,2-diyl, cyclobut-1-en-1,2-diyl,buta-1,3-dien-1,2-diyl, cyclobuta-1,3-dien-1,2-diyl, but-3-yn-1,2-diyl,etc.; and the like. Where specific levels of saturation are intended,the nomenclature vic alkandiyl, vic alkendiyl and/or vic alkyndiyl isused. In preferred embodiments, the vic alkyldiyl group is (C₂₋₈) vicalkyldiyl, with (C₂₋₃) being particularly preferred.

[0036] “Gem Alkyldiyl:” refers to a saturated or unsaturated, branched,straight-chain or cyclic hydrocarbon radical having one divalent radicalcenter derived by the removal of two hydrogen atoms from a single carbonatom of a parent alkane, alkene or alkyne. The divalent radical centerforms bonds with two different atoms. Typical gem alkyldiyls include,but are not limited to gem methanyldiyl; gem ethyldiyls such asethan-1,1-diyl,ethen-1,1-diyl; gem propyldiyls such as propan-1,1-diyl,propan-2,2-diyl, cyclopropan-1,1-diyl, prop-1-en-1,1-diyl,cycloprop-2-en-1,1-diyl, prop-2-yn-1,1-diyl, etc.; butyldiyls such asbutan-1,1-diyl, butan-2,2-diyl, 2-methyl-propan-1,2-diyl,cyclobutan-1,1-diyl, but-1-en-1,1-diyl, 2-methyl-prop-1-en-1,1-diyl,2-methyl-prop-2-en-1,1-diyl, cyclobut-2-en-1,1-diyl,buta-1,3-dien-1,1-diyl, etc.; and the like. Where specific levels ofsaturation are intended, the nomenclature gem alkandiyl, gem alkendiyland/or gem alkyndiyl is used. In preferred embodiments, the gemalkyldiyl group is (C₁₋₆) gem alkyldiyl, with (C₁₋₃) being particularlypreferred.

[0037] “Alkyleno:” refers to a saturated or unsaturated, straight-chainor branched acyclic bivalent hydrocarbon bridge radical derived by theremoval of one hydrogen atom from each of the two terminal carbon atomsof an acyclic parent alkane, alkene or alkyne. Typical alkyleno groupsinclude, but are not limited to, methano; ethylenos such as ethano,etheno, ethyno; propylenos such as propano, propeno, prop-1,2-dieno,propyno, etc.; butylenos such as butano, 2-methyl-propano, but-1-eno,but-2-eno, 2-methyl-prop-1-eno, 2-methanylidene-propano, but-1,3-dieno,but-1-yno, but-2-yno, but-1,3-diyno, etc.; and the like. Where specificlevels of saturation are intended, the nomenclature alkano, alkenoand/or alkyno is used. In preferred embodiments, the alkyleno group is(C₁₋₈) alkyleno, with (C₁₋₃) being particularly preferred. Alsopreferred are straight-chain saturated alkano radicals, e.g., methano,ethano, propano, butano, and the like.

[0038] “Alkylidene:” refers to a saturated or unsaturated, branched,straight-chain or cyclic divalent hydrocarbon radical derived by removalof two hydrogen atoms from the same carbon atom of a parent alkane,alkene or alkyne. The divalent radical center forms a double bond with asingle atom. Typical alkylidene radicals include, but are not limitedto, methanylidene, ethylidenes such as ethanylidene, ethenylidene;propylidenes such as propan-1-ylidene, propan-2-ylidene,cyclopropan-1-ylidene, prop-1-en-1-ylidene, prop-2-en-1-ylidene,cycloprop-2-en-1-ylidene, etc.; butylidenes such as butan-1-ylidene,butan-2-ylidene, 2-methyl-propan-1-ylidene, cyclobutan-1-ylidene,but-1-en-1-ylidene, but-2-en-1-ylidene, but-3-en-1-ylidene,buta-1,3-dien-1-ylidene; cyclobut-2-en-1-ylidene, etc.; and the like.Where specific levels of saturation are intended, the nomenclaturealkanylidene, alkenylidene and/or alkynylidene is used. In preferredembodiments, the alkylidene group is (C₁₋₈) alkylidene, with (C₁₋₃)being particularly preferred. Also preferred are acyclic saturatedalkanylidene radicals in which the divalent radical is at a terminalcarbon, e.g., methanylidene, ethan-1-ylidene, propan-1-ylidene,butan-1-ylidene, 2-methyl-propan-1-ylidene, and the like.

[0039] “Alkylidyne:” refers to a saturated or unsaturated, branched orstraight-chain trivalent hydrocarbon radical derived by removal of threehydrogen atoms from the same carbon atom of a parent alkane, alkene oralkyne. The trivalent radical center forms a triple bond with a singleatom. Typical alkylidyne radicals include, but are not limited to,methanylidyne; ethanylidyne; propylidynes such as propan-1-ylidyne,prop-2-en-1-ylidyne, prop-2-yn-1-ylidyne; butylidynes such asbutan-1-ylidyne, 2-methyl-propan-1-ylidyne, but-2-en-1-ylidyne,but-3-en-1-ylidyne, buta-2,3-dien-1-ylidyne, but-2-yn-1-ylidyne,but-3-yn-1-ylidyne, etc.; and the like. Where specific levels ofsaturation are intended, the nomenclature alkanylidyne, alkenylidyneand/or alkynylidyne is used. In preferred embodiments, the alkylidynegroup is (C₁₋₈) alkylidyne, with (C₁₋₃) being particularly preferred.Also preferred are saturated alkanylidyne radicals, e.g., methanylidyne,ethanylidyne, propan-1-ylidyne, butan-1-ylidyne,2-methyl-propan-1-ylidyne, and the like.

[0040] “Heteroalkyl, Heteroalkanyl, Heteroalkenyl, Heteroalkynyl,Heteroalkylidene, Heteroalkylidyne, Heteroalkyldiyl, Vic Heteralkyldiyl,Gem Heteroalkyldivl, Heteroalkyleno and Heteroalkyldiylidene:” refer toalkyl, alkanyl, alkenyl, alkynyl, alkylidene, alkylidyne, alkyldiyl, vicalkyldiyl, gem alkyldiyl, alkyleno and alkyldiylidene radicals,respectively, in which one or more carbon atoms (and any necessaryassociated hydrogen atoms) are independently replaced with the same ordifferent heteroatoms (including any necessary hydrogen or other atoms).Typical heteroatoms to replace the carbon atom(s) include, but are notlimited to, N, P, O, S, Si, etc. Preferred heteroatoms are O, N and S.Thus, heteroalkyl, heteroalkanyl, heteroalkenyl, heteroalkynyl,heteroalkylidene, heteroalkylidyne, heteroalkyldiyl, vicheteroalkyldiyl, gem heteroalkyldiyl, heteroalkyleno andheteroalkyldiylidene radicals can contain one or more of the same ordifferent heteroatomic groups, including, by way of example and notlimitation, epoxy (—O—), epidioxy (—O—O—), thioether (—S—), epidithio(—SS—), epoxythio (—O—S—), epoxyimino (—O—NR′—), imino (—NR′—), biimmino(—NR′—NR′—), azino (═N—N═), azo (—N═N—), azoxy (—N—O—N—), azimino(—NR′—N═N—), phosphano (—PH—), λ⁴-sulfano (—SH₂—), sulfonyl (—S(O)₂—),and the like, where each R′ is independently hydrogen or (C₁-C₆) alkyl.

[0041] “Parent Aromatic Ring System:” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more rings are aromaticand one or more rings are saturated or unsaturated, such as, forexample, indane, indene, phenalene, etc. Typical parent aromatic ringsystems include, but are not limited to, aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like

[0042] “Aryl:” refers to a monovalent aromatic hydrocarbon radicalderived by the removal of one hydrogen atom from a single carbon atom ofa parent aromatic ring system. Typical aryl groups include, but are notlimited to, radicals derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like. In preferredembodiments, the aryl group is (C₅₋₂₀) aryl, with (C₅₋₁₀) beingparticularly preferred. Particularly preferred aryl groups are phenyland naphthyl groups.

[0043] “Arylalkyl:” refers to an acyclic alkyl group in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal carbonatom, is replaced with an aryl radical. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. Where specific alkyl moieties are intended, the nomenclaturearylalkanyl, arylakenyl and/or arylalkynyl is used. [In preferredembodiments, the arylalkyl group is (C₆₋₂₆) arylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C₁₋₆) andthe aryl moiety is (C₅₋₂₀). In particularly preferred embodiments thearylalkyl group is (C₆₋₁₃), e.g., the alkanyl, alkenyl or alkynyl moietyof the arylalkyl group is (C₁₋₃) and the aryl moiety is (C₅₋₁₀). Evenmore preferred arylalkyl groups are phenylalkanyls.

[0044] “Alkanyloxy:” refers to a saturated branched, straight-chain orcyclic monovalent hydrocarbon alcohol radical derived by the removal ofthe hydrogen atom from the hydroxide oxygen of the alcohol. Typicalalkanyloxy groups include, but are not limited to, methanyl; ethanyloxy;propanyloxy groups such as propan-1-yloxy (CH₃CH₂CH₂O—), propan-2-yloxy((CH₃)₂CHO—), cyclopropan-1-yloxy, etc.; butyanyloxy groups such asbutan-1-yloxy, butan-2-yloxy, 2-methyl-propan-1-yloxy,2-methyl-propan-2-yloxy, cyclobutan-1-yloxy, etc.; and the like. Inpreferred embodiments, the alkanyloxy groups are (C₁₋₈) alkanyloxygroups, with (C₁₋₃) being particularly preferred.

[0045] “Parent Heteroaromatic Ring System:” refers to a parent aromaticring system in which one or more carbon atoms are each independentlyreplaced with a heteroatom. Typical heteratoms to replace the carbonatoms include, but are not limited to, N, P, O, S, Si etc. Specificallyincluded within the definition of “parent heteroaromatic ring systems”are fused ring systems in which one or more rings are aromatic and oneor more rings are saturated or unsaturated, such as, for example,arsindole, chromane, chromene, indole, indoline, xanthene, etc. Typicalparent heteroaromatic ring systems include, but are not limited to,arsindole, carbazole, β-carboline, chromane, chromene, cinnoline, furan,imidazole, indazole, indole, indoline, indolizine, isobenzofuran,isochromene, isoindole, isoindoline, isoquinoline, isothiazole,isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike.

[0046] “Heteroaryl:” refers to a monovalent heteroaromatic radicalderived by the removal of one hydrogen atom from a single atom of aparent heteroaromatic ring system. Typical heteroaryl groups include,but are not limited to, radicals derived from acridine, arsindole,carbazole, f,-carboline, chromane, chromene, cinnoline, furan,imidazole, indazole, indole, indoline, indolizine, isobenzofuran,isochromene, isoindole, isoindoline, isoquinoline, isothiazole,isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike. In preferred embodiments, the heteroaryl group is a 5-20 memberedheteroaryl, with 5-10 membered heteroaryl being particularly preferred.Specific preferred heteroaryls for the present invention are quinoline,isoquinoline, pyridine, pyrimidine, furan, thiophene and imidazole.

[0047] “Substituted:” refers to a radical in which one or more hydrogenatoms are each independently replaced with the same or differentsubstituent(s). Typical substituents include, but are not limited to,—X, —R, —O—, ═O, —OR, —O—OR, —SR, —S⁻, ═S, —NRR, ═NR, —CX₃, —CN, —OCN,—SCN, —NCO, —NCS, —NO, —NO₂, ═N₂, —N₃, —NHOH, —S(O)₂O⁻, —S(O)₂OH,—S(O)₂R, —P(O)(O⁻)₂, —P(O)(OH)₂, —C(O)R, —C(O)X, —C(S)R, —C(S)X,—C(O)OR, —C(O)O⁻, —C(S)OR, —C(O)SR, —C(S)SR, —C(O)NRR, —C(S)NRR and—C(NR)NRR, where each X is independently a halogen (preferably —F, —Clor —Br) and each R is independently —H, alkyl, alkanyl, alkenyl,alkynyl, alkylidene, alkylidyne, aryl, arylalkyl, arylheteroalkyl,heteroaryl, heteroarylalkyl or heteroaryl-heteroalkyl, as definedherein. Preferred substituents include hydroxy, halogen, C₁₋₈alkyl,C₁₋₈alkanyloxy, fluorinated alkanyloxy, fluorinated alkyl,C₁₋₈alkylthio, C₃₋₈cycloalkyl, C₃₋₈cycloalkanyloxy, nitro, amino,C₁₋₈alkylamino, C₁₋₈dialkylamino, C₃₋₈cycloalkylamino, cyano, carboxy,C₁₋₇alkanyloxycarbonyl, C₁₋₇alkylcarbonyloxy, formyl, carbamoyl, phenyl,aroyl, carbamoyl, amidino, (C₁₋₈alkylamino)carbonyl, (arylamino)carbonyland aryl(C₁₋₈alkyl)carbonyl.

[0048] “Aroyl” refers to arylacyl substituents.

[0049] “Acyl” refers to alkylcarbonyl substituents.

[0050] With reference to substituents, the term “independently” meansthat when more than one of such substituent is possible, suchsubstituents may be the same or different from each other.

[0051] Throughout this disclosure, the terminal portion of thedesignated side chain is described first, followed by the adjacentfunctionality toward the point of attachment. Thus, for example, a“phenylC₁₋₆alkanylaminocarbonylC₁₋₆alkyl” substituent refers to a groupof the formula

[0052] The present invention is directed to compositions comprising acompound of Formula (I):

[0053] wherein R₁ independently may be absent or an optionallysubstituted substituent selected from alkyl, heteroalkyl, aryl(preferably 5-10 membered aryl), arylalkyl, halogen, nitro, amino,cyano, carboxy, carbamoyl, aroyl, amidino, and acyl; n is an integerfrom 1 to 3; m is an integer from 0 to 3; R₂ may be absent or anoptionally substituted substituent selected from alkyl, heteroalkyl,aryl (preferably 5-10 membered aryl), heteroaryl (preferably 5-10membered heteroaryl), alkylidenyl, heteroalkylidenyl, alkylidynyl,heteroalkylidynyl, arylalkyl, halogen, nitro, amino, and cyano; L is adirect bond, alkyldiyl or heteroalkyldiyl; R₃ is aryl (preferably 5-10membered aryl) or heteroaryl (preferably 5-10 membered heteroaryl); R₄and R₅ are hydrogen, alkyl, or heteroalkyl; X is O or S; andenantiomers, diastereomers, tautomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0054] In particular, the present invention is directed to compounds ofFormula (I) wherein:

[0055] R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₁₋₈alkanyloxy optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl;C₁₋₈alkanylthio optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy;nitro; amino; C₁₋₈alkanylamino; C₁₋₈dialkanylamino;C₃₋₈cycloalkanylamino; cyano; carboxy; C₁₋₇alkanyloxycarbonyl;C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl; phenyl optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxyl, nitro, amino and cyano; aroyl;carbamoyl; amidino; (C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl;

[0056] n is an integer from 1 to 3;

[0057] m is an integer from 0 to 3;

[0058] R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; ; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino;

[0059] L is a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl,or C₃₋₈cycloalkandiyl;

[0060] R₃ is selected from the group consisting of phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; naphthyl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl,nitro, amino, di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; andheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₈alkanyl,halogen, nitro, amino and cyano wherein said heteroaryl is quinolinyl,quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;

[0061] R₄ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0062] R₅ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0063] X is selected from the group consisting of O and S; and

[0064] enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.

[0065] Preferred embodiments of the present invention are those inwhich: (1) R₁ is a substituent independently selected from the groupconsisting of hydrogen, hydroxy, fluoro, chloro, bromo, andC₁₋₈alkanyloxy; (2) R₁ is a substituent independently selected from thegroup consisting of fluoro, chloro, bromo, C₁₋₈alkanyloxy, (3) R₂ isindependently selected from the group consisting of hydrogen,C₂₋₈alkenyl, C₁₋₈alkylidenyl, C₁₋₈alkylidynyl, C₃₋₈cycloalkanyl, phenyl(optionally substituted with one to three substituents independentlyselected from the group consisting of fluoro, chloro, bromo, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, and fluorinatedalkanyl), naphthyl (optionally substituted with one to threesubstituents independently selected from the group consisting of fluoro,chloro, bromo, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, and fluorinated alkanyl), and a heteroaryloptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₆alkanyl and halogen whereinthe heteroaryl is pyridyl, pyrimidyl, furyl, thienyl or imidazolyl; (4)L is a direct bond or C₁₋₈alkandiyl; (5) R₃ is selected from the groupconsisting of naphthyl substituted with hydroxyl; quinolinyl andisoquinolinyl; and (6) any combination of (1) to (5) preceding. Thus,preferred embodiments of the present invention are as described below.

[0066] An embodiment of the present invention is directed tocompositions comprising a compound of Formula (I) wherein:

[0067] R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; fluoro; chloro; and C₁₋₈alkanyloxy;

[0068] n is an integer from 1 to 3;

[0069] m is an integer from 0 to 3;

[0070] R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino;

[0071] L is a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl,or C₃₋₈cycloalkandiyl;

[0072] R₃ is selected from the group consisting of phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; naphthyl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl,nitro, amino, di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; andheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₈alkanyl,halogen, nitro, amino and cyano wherein said heteroaryl is quinolinyl,quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;

[0073] R₄ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0074] R₅ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0075] X is selected from the group consisting of O and S; andenantiomers, diastereomers, tautomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0076] Another embodiment of the present invention is directed tocompositions comprising a compound of Formula (I) wherein:

[0077] R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₁₋₈alkanyloxy optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl;C₁₋₈alkanylthio optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy;nitro; amino; C₁₋₈alkanylamino; C₁₋₈dialkanylamino;C₃₋₈cycloalkanylamino; cyano; carboxy; C₁₋₇alkanyloxycarbonyl;C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl; phenyl optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxyl, nitro, amino and cyano; aroyl;carbamoyl; amidino; (C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl;

[0078] n is an integer from 1 to 3;

[0079] m is an integer from 0 to 3;

[0080] R₂ is independently selected from the group consisting ofhydrogen; C₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl;C₃₋₈cycloalkanyl; phenyl optionally substituted with one to threesubstituents independently selected from the group consisting of fluoro,chloro, bromo, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of fluoro, chloro, bromo, hydroxy, C₁₋₈alkanyl,C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl; and aheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₆alkanyl andhalogen wherein said heteroaryl is pyridyl, pyrimidyl, furyl, thienyl orimidazolyl;

[0081] L is a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl,or C₃₋₈cycloalkandiyl;

[0082] R₃ is selected from the group consisting of phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; naphthyl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl,nitro, amino, di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; andheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₈alkanyl,halogen, nitro, amino and cyano wherein said heteroaryl is quinolinyl,quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;

[0083] R₄ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0084] R₅ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0085] X is selected from the group consisting of O and S; andenantiomers, diastereomers, tautomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0086] Still another embodiment of the present invention is directed tocompositions comprising a compound of Formula (I) wherein:

[0087] R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₁₋₈alkanyloxy optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl;C₁₋₈alkanylthio optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy;nitro; amino; C₁₋₈alkanylamino; C₁₋₈dialkanylamino;C₃₋₈cycloalkanylamino; cyano; carboxy; C₁₋₇alkanyloxycarbonyl;C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl; phenyl optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxyl, nitro, amino and cyano; aroyl;carbamoyl; amidino; (C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl;

[0088] n is an integer from 1 to 3;

[0089] m is an integer from 0 to 3;

[0090] R₂ is independently selected from the group consisting ofhydrogen; C₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl;C₃₋₈cycloalkanyl; phenyl optionally substituted with one to threesubstituents independently selected from the group consisting of fluoro,chloro, bromo, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy and fluorinatedalkanyl; naphthyl optionally substituted with one to three substituentsindependently selected from the group consisting of fluoro, chloro,bromo, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy and fluorinated alkanyl;pyridyl; pyrimidyl; furyl; thienyl and imidazolyl.

[0091] L is a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl,or C₃₋₈cycloalkandiyl;

[0092] R₃ is selected from the group consisting of phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; naphthyl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl,nitro, amino, di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; andheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₈alkanyl,halogen, nitro, amino and cyano wherein said heteroaryl is quinolinyl,quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;

[0093] R₄ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0094] R₅ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0095] X is selected from the group consisting of O and S; andenantiomers, diastereomers, tautomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0096] Furthermore, another embodiment of the present invention isdirected to compositions comprising a compound of Formula (I) wherein:

[0097] R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₁₋₈alkanyloxy optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl;C₁₋₈alkanylthio optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy;nitro; amino; C₁₋₈alkanylamino; C₁₋₈dialkanylamino;C₃₋₈cycloalkanylamino; cyano; carboxy; C₁₋₇alkanyloxycarbonyl;C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl; phenyl optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxyl, nitro, amino and cyano; aroyl;carbamoyl; amidino; (C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl;

[0098] n is an integerfrom 1 to 3;

[0099] m is an integer from 0 to 3;

[0100] R₂ is independently selected from the group consisting ofC₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl; C₃₋₈cycloalkanyl; phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of fluoro, chloro, bromo, andfluorinated alkanyl.

[0101] L is a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl,or C₃₋₈cycloalkandiyl;

[0102] R₃ is selected from the group consisting of phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; naphthyl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl,nitro, amino, di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; andheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₈alkanyl,halogen, nitro, amino and cyano wherein said heteroaryl is quinolinyl,quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;

[0103] R₄ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0104] R₅ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0105] X is selected from the group consisting of O and S; andenantiomers, diastereomers, tautomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0106] An embodiment of the present invention is directed tocompositions comprising a compound of Formula (I) wherein:

[0107] R₁ is a substituent independently selected from the groupconsisting of fluoro; chloro; C₁₋₈alkanyloxy;

[0108] n is an integer from 1 to 3;

[0109] m is an integer from 0 to 3;

[0110] R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino;

[0111] L is a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl,or C₃₋₈cycloalkandiyl;

[0112] R₃ is selected from the group consisting of phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; naphthyl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl,nitro, amino, di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; andheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₈alkanyl,halogen, nitro, amino and cyano wherein said heteroaryl is quinolinyl,quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;

[0113] R₄ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0114] R₅ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0115] X is selected from the group consisting of O and S; andenantiomers, diastereomers, tautomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0116] Another embodiment of the present invention is directed tocompositions comprising a compound of Formula (I) wherein:

[0117] R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₁₋₈alkanyloxy optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl;C₁₋₈alkanylthio optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy;nitro; amino; C₁₋₈alkanylamino; C₁₋₈dialkanylamino;C₃₋₈cycloalkanylamino; cyano; carboxy; C₁₋₇alkanyloxycarbonyl;C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl; phenyl optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxyl, nitro, amino and cyano; aroyl;carbamoyl; amidino; (C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl;

[0118] n is 1;

[0119] m is an integer from 0 to 3;

[0120] R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino;

[0121] L is a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl,or C₃₋₈cycloalkandiyl;

[0122] R₃ is selected from the group consisting of phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₁₈)alkanylamino,C₁₋₈alkanylamino and cyano; naphthyl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl,nitro, amino, di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; andheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₈alkanyl,halogen, nitro, amino and cyano wherein said heteroaryl isquinolinyl,quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide,pyridyl, pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;

[0123] R₄ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0124] R₅ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0125] X is selected from the group consisting of O and S; andenantiomers, diastereomers, tautomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0126] Still yet another embodiment of the present invention is directedto compositions comprising a compound of Formula (I) wherein:

[0127] R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₁₋₈alkanyloxy optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl;C₁₋₈alkanylthio optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy;nitro; amino; C₁₋₈alkanylamino; C₁₋₈dialkanylamino;C₃₋₈cycloalkanylamino; cyano; carboxy; C₁₋₇alkanyloxycarbonyl;C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl; phenyl optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxyl, nitro, amino and cyano; aroyl;carbamoyl; amidino; (C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl;

[0128] n is an integer from 1 to 3;

[0129] m is an integer from 0 to 1;

[0130] R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino;

[0131] L is a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl,or C₃₋₈cycloalkandiyl;

[0132] R₃ is selected from the group consisting of phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; naphthyl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl,nitro, amino, di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; andheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₈alkanyl,halogen, nitro, amino and cyano wherein said heteroaryl isquinolinyl,quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide,pyridyl, pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;

[0133] R₄ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0134] R₅ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0135] X is selected from the group consisting of O and S; andenantiomers, diastereomers, tautomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0136] Another embodiment of the present invention is directed tocompositions comprising a compound of Formula (I) wherein:

[0137] R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₁₋₈alkanyloxy optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl;C₁₋₈alkanylthio optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy;nitro; amino; C₁₋₈alkanylamino; C₁₋₈dialkanylamino;C₃₋₈cycloalkanylamino; cyano; carboxy; C₁₋₇alkanyloxycarbonyl;C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl; phenyl optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxyl, nitro, amino and cyano; aroyl;carbamoyl; amidino; (C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl;

[0138] n is an integer from 1 to 3;

[0139] m is 1;

[0140] R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino;

[0141] L is a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl,or C₃₋₈cycloalkandiyl;

[0142] R₃ is selected from the group consisting of phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; naphthyl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl,nitro, amino, di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; andheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₈alkanyl,halogen, nitro, amino and cyano wherein said heteroaryl is quinolinyl,quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;

[0143] R₄ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0144] R₅ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0145] X is selected from the group consisting of O and S; andenantiomers, diastereomers, tautomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0146] Another embodiment of the present invention is directed tocompositions comprising a compound of Formula (I) wherein:

[0147] R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₁₋₈alkanyloxy optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl;C₁₋₈alkanylthio optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy;nitro; amino; C₁₋₈alkanylamino; C₁₋₈dialkanylamino;C₃₋₈cycloalkanylamino; cyano; carboxy; C₁₋₇alkanyloxycarbonyl;C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl; phenyl optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxyl, nitro, amino and cyano; aroyl;carbamoyl; amidino; (C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl;

[0148] n is an integer from 1 to 3;

[0149] m is an integer from 0 to 3;

[0150] R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino;

[0151] L is a direct bond or C₁₋₈alkandiyl;

[0152] R₃ is selected from the group consisting of phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; naphthyl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl,nitro, amino, di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; andheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₈alkanyl,halogen, nitro, amino and cyano wherein said heteroaryl isquinolinyl,quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide,pyridyl, pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;

[0153] R₄ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0154] R₅ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0155] X is selected from the group consisting of O and S; andenantiomers, diastereomers, tautomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0156] Yet another embodiment of the present invention is directed tocompositions comprising a compound of Formula (I) wherein:

[0157] R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₁₋₈alkanyloxy optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl;C₁₋₈alkanylthio optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy;nitro; amino; C₁₋₈alkanylamino; C₁₋₈dialkanylamino;C₃₋₈cycloalkanylamino; cyano; carboxy; C₁₋₇alkanyloxycarbonyl;C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl; phenyl optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxyl, nitro, amino and cyano; aroyl;carbamoyl; amidino; (C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl;

[0158] n is an integer from 1 to 3;

[0159] m is an integer from 0 to 3;

[0160] R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino;

[0161] L is a direct bond;

[0162] R₃ is selected from the group consisting of phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; naphthyl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl,nitro, amino, di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; andheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₈alkanyl,halogen, nitro, amino and cyano wherein said heteroaryl is quinolinyl,quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;

[0163] R₄ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0164] R₅ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0165] X is selected from the group consisting of O and S; andenantiomers, diastereomers, tautomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0166] Still yet another embodiment of the present invention is directedto compositions comprising a compound of Formula (I) wherein:

[0167] R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₁₋₈alkanyloxy optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl;C₁₋₈alkanylthio optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy;nitro; amino; C₁₋₈alkanylamino; C₁₋₈dialkanylamino;C₃₋₈cycloalkanylamino; cyano; carboxy; C₁₋₇alkanyloxycarbonyl;C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl; phenyl optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxyl, nitro, amino and cyano; aroyl;carbamoyl; amidino; (C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl;

[0168] n is an integer from 1 to 3;

[0169] m is an integer from 0 to 3;

[0170] R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino;

[0171] L is a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl,or C₃₋₈cycloalkandiyl;

[0172] R₃ is selected from the group consisting of phenyl substitutedwith one to three substituents independently selected from the groupconsisting of C₁₋₈alkanyl, fluoro, chloro, bromo, C₁₋₈alkanyloxy,hydroxy, fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; naphthyl substituted with one to threesubstituents independently selected from the group consisting ofC₁₋₈alkanyl, fluoro, chloro, bromo, C₁₋₈alkanyloxy, hydroxy, fluorinatedalkanyl, nitro, amino, di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano;and heteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₈alkanyl, fluoroand chloro, wherein said heteroaryl is quinolinyl-N-oxide,isoquinolinyl, isoquinolinyl-N-oxide, pyridyl, pyridyl-N-oxide,pyrimidyl, furyl, thienyl or imidazolyl;

[0173] R₄ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0174] R₅ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0175] X is selected from the group consisting of O and S; andenantiomers, diastereomers, tautomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0176] Furthermore, another embodiment of the present invention isdirected to compositions comprising a compound of Formula (I) wherein:

[0177] R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₁₋₈alkanyloxy optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl;C₁₋₈alkanylthio optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy;nitro; amino; C₁₋₈alkanylamino; C₁₋₈dialkanylamino;C₃₋₈cycloalkanylamino; cyano; carboxy; C₁₋₇alkanyloxycarbonyl;C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl; phenyl optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxyl, nitro, amino and cyano; aroyl;carbamoyl; amidino; (C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl;

[0178] n is an integer from 1 to 3;

[0179] m is an integer from 0 to 3;

[0180] R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino;

[0181] L is a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl,or C₃₋₈cycloalkandiyl;

[0182] R₃ is selected from the group consisting of phenyl substitutedwith one to three substituents independently selected from the groupconsisting of C₁₋₈alkanyloxy and hydroxy; naphthyl substituted with oneto three substituents independently selected from the group consistingof C₁₋₈alkanyloxy and hydroxy; and heteroaryl optionally substitutedwith one to three substituents independently selected from the groupconsisting of C₁₋₈alkanyl and chloro wherein said heteroaryl isquinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl andpyridyl-N-oxide;

[0183] R₄ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0184] R₅ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0185] X is selected from the group consisting of O and S; andenantiomers, diastereomers, tautomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0186] Another embodiment of the present invention is directed tocompositions comprising a compound of Formula (I) wherein

[0187] R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₁₋₈alkanyloxy optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl;C₁₋₈alkanylthio optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy;nitro; amino; C₁₋₈alkanylamino; C₁₋₈dialkanylamino;C₃₋₈cycloalkanylamino; cyano; carboxy; C₁₋₇alkanyloxycarbonyl;C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl; phenyl optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxyl, nitro, amino and cyano; aroyl;carbamoyl; amidino; (C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl;

[0188] n is an integer from 1 to 3;

[0189] m is an integer from 0 to 3;

[0190] R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino;

[0191] L is a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl,or C₃₋₈cycloalkandiyl;

[0192] R₃ is selected from the group consisting of naphthyl substitutedwith hydroxyl; quinolinyl optionally substituted with one or moresubstituents selected from the group consisting of methyl and chloro,quinolinyl-N-oxide, isoquinolinyl optionally substituted with one ormore substituents selected from the group consisting of methyl andchloro and isoquinolinyl-N-oxide;

[0193] R₄ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0194] R₅ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0195] X is selected from the group consisting of O and S; andenantiomers, diastereomers, tautomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0196] Another embodiment of the present invention is directed tocompositions comprising a compound of Formula (I) wherein:

[0197] R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallyindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, fluorinated alkanyl andC₁₋₈alkanyloxy; C₁₋₈alkanyloxy optionally independently substituted withone or more substituents independently selected from the groupconsisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;fluorinated alkanyloxy; fluorinated alkanyl; C₁₋₈alkanylthio optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy; nitro; amino; C₁₋₈alkanylamino;C₁₋₈dialkanylamino; C₃₋₈cycloalkanylamino; cyano; carboxy;C₁₋₇alkanyloxycarbonyl; C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl;phenyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxyl,nitro, amino and cyano; aroyl; carbamoyl; amidino;(C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl;

[0198] n is an integer from 1 to 3;

[0199] m is an integer from 0 to 3;

[0200] R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroarylis pyridyl, pyrimidyl,furyl, thienyl or imidazolyl; pyrrolidino; and piperidino;

[0201] L is a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl,or C₃₋₈cycloalkandiyl;

[0202] R₃ is 2-hydroxynaphth-8-yl, isoquinolin-5-yl andisoquinolinyl-5-yl-N-oxide;

[0203] R₄ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0204] R₅ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0205] X is selected from the group consisting of O and S; andenantiomers, diastereomers, tautomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0206] Yet another embodiment of the present invention is directed tocompositions comprising a compound of Formula (I) wherein:

[0207] R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₁₋₈alkanyloxy optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl;C₁₋₈alkanylthio optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy;nitro; amino; C₁₋₈alkanylamino; C₁₋₈dialkanylamino;C₃₋₈cycloalkanylamino; cyano; carboxy; C₁₋₇alkanyloxycarbonyl;C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl; phenyl optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxyl, nitro, amino and cyano; aroyl;carbamoyl; amidino; (C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl;

[0208] n is an integer from 1 to 3;

[0209] m is an integer from 0 to 3;

[0210] R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino;

[0211] L is a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl,or C₃₋₈cycloalkandiyl;

[0212] R₃ is selected from the group consisting of phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; naphthyl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl,nitro, amino, di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; andheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₈alkanyl,halogen, nitro, amino and cyano wherein said heteroaryl is quinolinyl,quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;

[0213] R₄ is hydrogen;

[0214] R₅ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0215] X is selected from the group consisting of O and S; andenantiomers, diastereomers, tautomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0216] Still yet another embodiment of the present invention is directedto compositions comprising a compound of Formula (I) wherein:

[0217] R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₁₋₈alkanyloxy optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl;C₁₋₈alkanylthio optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy;nitro; amino; C₁₋₈alkanylamino; C₁₋₈dialkanylamino;C₃₋₈cycloalkanylamino; cyano; carboxy; C₁₋₇alkanyloxycarbonyl;C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl; phenyl optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxyl, nitro, amino and cyano; aroyl;carbamoyl; amidino; (C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl;

[0218] n is an integer from 1 to 3;

[0219] m is an integer from 0 to 3;

[0220] R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino;

[0221] L is a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl,or C₃₋₈cycloalkandiyl;

[0222] R₃ is selected from the group consisting of phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; naphthyl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl,nitro, amino, di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; andheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₈alkanyl,halogen, nitro, amino and cyano wherein said heteroaryl is quinolinyl,quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;

[0223] R₄ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0224] R₅ is hydrogen;

[0225] X is selected from the group consisting of O and S; andenantiomers, diastereomers, tautomers, solvates, and pharmaceuticallyacceptable salts thereof.

[0226] Furthermore, another embodiment of the present invention isdirected to compositions comprising a compound of Formula (I) wherein:

[0227] R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₁₋₈alkanyloxy optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; fluorinated alkanyloxy; fluorinated alkanyl;C₁₋₈alkanylthio optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy; C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy;nitro; amino; C₁₋₈alkanylamino; C₁₋₈dialkanylamino;C₃₋₈cycloalkanylamino; cyano; carboxy; C₁₋₇alkanyloxycarbonyl;C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl; phenyl optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxyl, nitro, amino and cyano; aroyl;carbamoyl; amidino; (C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl;

[0228] n is an integer from 1 to 3;

[0229] m is an integer from 0 to 3;

[0230] R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino;

[0231] L is a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl,or C₃₋₈cycloalkandiyl;

[0232] R₃ is selected from the group consisting of phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; naphthyl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl,nitro, amino, di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; andheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₈alkanyl,halogen, nitro, amino and cyano wherein said heteroaryl isquinolinyl,quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide,pyridyl, pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl;

[0233] R₄ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0234] R₅ is selected from the group consisting of hydrogen andC₁₋₈alkanyl;

[0235] X is O; and enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.

[0236] Another embodiment of the present invention is directed tocompositions comprising a compound of Formula (Ia):

[0237] the compound selected from the group consisting of:

[0238] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is 3-Pyridinyl,m is 1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0239] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is H, m is 0,L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0240] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0241] a compound of formula (Ia) wherein R₁ is H, R₂ is 3-Pyridinyl, mis 1, L is —CH₂—, R₃ is (3-OMe-4-(Methoxymethyleneoxy)Ph, and X is S;

[0242] a compound of formula (Ia) wherein R₁ is H, R₂ is 3-Pyridinyl, mis 1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0243] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is3-Pyridinyl, m is 1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0244] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is —CH═CH₂ mis 1, L is —CH₂—, R₃ is (3-OMe-4-(Methoxymethyleneoxy)Ph, and X is S;

[0245] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is4-Imidazolyl, m is 1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0246] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂—, R₃ is (3,4-methylenedioxy)Ph, and X is O;

[0247] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂—, R₃ is (3,4-diOMe)Ph, and X is O;

[0248] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂—, R₃ is (4-tBu)Ph, and X is O;

[0249] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂CH₂—, R₃ is (4-Cl)Ph, and X is O;

[0250] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂CH₂—, R₃ is (3,4-diOMe)Ph, and X is O;

[0251] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂—, R₃ is (3,4-methylenedioxy)Ph, and X is S;

[0252] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂—, R₃ is (3,4-diOMe)Ph, and X is S;

[0253] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂—, R₃ is (4-tBu)Ph, and X is S;

[0254] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂CH₂—, R₃ is (4-Cl)Ph, and X is S;

[0255] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂CH₂—, R₃ is (3,4-diOMe)Ph, and X is S;

[0256] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is O;

[0257] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH═CH—O, R₃ is (3-OMe-4-OH)Ph, and X is O;

[0258] a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is (3-OMe-4-(Methoxymethyleneoxy)Ph, and X is S;

[0259] a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0260] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂—, R₃ is (4-N(Me)(C₅H₁₁))Ph, and X is O;

[0261] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂—, R₃ is (4-[N(Me)(cyclohexyl)])Ph, and X is O;

[0262] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is (3,4-diOMe)Ph, and X is S;

[0263] a compound of formula (Ia) wherein R, is 6-OMe, R₂ is Ph, m is 1,L is —CH₂—, R₃ is (4-CF₃)Ph, and X is O;

[0264] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂—, R₃ is (3,4-diCl)Ph, and X is O;

[0265] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂CH₂—, R₃ is (3,4-diCl)Ph, and X is O;

[0266] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂—, R₃ is (4-CF₃)Ph, and X is S;

[0267] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂—, R₃ is (3,4-diCl)Ph, and X is S;

[0268] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂CH₂—, R₃ is (3,4-diCl)Ph, and X is S;

[0269] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0270] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is a direct bond, R₃ is 3-quinolinyl, and X is O;

[0271] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is a direct bond, R₃ is 8-(2-naphtholyl), and X is O;

[0272] a compound of formula (Ia) wherein R₁ is H, R₂ is H, m is O, L isa direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0273] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is H, m is 0, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0274] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0275] a compound of formula (Ia) wherein R₁ is 6-Br, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0276] a compound of formula (Ia) wherein R₁ is 6,7-diOMe, R₂ is Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0277] a compound of formula (Ia) wherein R₁ is 7-Cl, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0278] a compound of formula (Ia) wherein R₁ is 5-Cl, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0279] a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0280] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (3-Cl)Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0281] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is3-Pyridinyl, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X isO;

[0282] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (3-Cl)Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0283] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is3-Pyridinyl, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X isO;

[0284] a compound of formula (Ia) wherein R₁ is 6,7-diOMe, R₂ is Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0285] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (2-Cl)Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0286] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-Cl)Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0287] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is H, m is 0,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0288] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (2-Cl)Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0289] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (2-CF₃)Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0290] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (3-CF₃)Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0291] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-CF₃)Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0292] a compound of formula (Ia) wherein R₁ is 6-OH, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0293] a compound of formula (Ia) wherein R₁ is H, R₂ is —CH═CH₂, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0294] a compound of formula (Ia) wherein R₁ is 6-Br, R₂ is H, m is 0, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0295] a compound of formula (Ia) wherein R₁ is 6-Cl, R₂ is H, m is 0, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0296] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is 5-isoquinolinyl, and X is O;

[0297] a compound of formula (Ia) wherein R₁ is 7-C₁, R₂ is H, m is 0, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0298] a compound of formula (Ia) wherein R₁ is 8-C₁, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0299] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-CN)Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0300] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-Br)Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0301] a compound of formula (Ia) wherein R₁ is 6-C₁, R₂ is CN, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0302] a compound of formula (Ia) wherein R₁ is 6,7-diF, R₂ is Ph, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0303] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 8-(2-naphtholyl), and X is O;

[0304] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is —CH═CH₂, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0305] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is —CH═CH₂, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0306] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-OMe)Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0307] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Cyclopropyl,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0308] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-OMe)Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0309] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (2-OMe)Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0310] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is(4-Benzyloxy)Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, andX is O;

[0311] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂—, R₃ is 4-Pyridinyl, and X is O;

[0312] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is 2-Thienyl, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0313] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is(2,6-diF)Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X isO;

[0314] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is —CH₂═CH₂, mis 1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0315] a compound of formula (Ia) wherein R₁ is 7-F, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0316] a compound of formula (Ia) wherein R₁ is 5-F, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0317] a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0318] a compound of formula (Ia) wherein R₁ is H, R₂ is H, m is 1, L is—CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0319] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is H, m is 1, Lis —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0320] a compound of formula (Ia) wherein R₁ is H, R₂ is Cyclopropyl, mis 1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0321] a compound of formula (Ia) wherein R₁ is H, R₂ is 3-thienyl, m is1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0322] a compound of formula (Ia) wherein R₁ is H, R₂ is 2-thienyl, m is1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0323] a compound of formula (Ia) wherein R₁ is H, R₂ is 3-furyl, m is1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0324] a compound of formula (Ia) wherein R₁ is H, R₂ is 2-furyl, m is1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0325] a compound of formula (Ia) wherein R₁ is H, R₂ is 4-pyridinyl, mis 1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0326] a compound of formula (Ia) wherein R₁ is H, R₂ is 3-pyridinyl, mis 1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0327] a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis —CH₂CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0328] a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis —CH₂CH(Me)—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0329] a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis —CH(Me)CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0330] a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis —CH₂CH₂—, R₃ is (3-OMe-4-OCH₂CH₂NH₂)Ph, and X is S;

[0331] a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis —CH₂CH(Me)—, R₃ is (3-OMe-4-OCH₂CH₂NH₂)Ph, and X is S;

[0332] a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis —CH(Me)CH₂—, R₃ is (3-OMe-4-OCH₂CH₂NH₂)Ph, and X is S;

[0333] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂—, R₃ is 4-pyridinyl, and X is S;

[0334] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is 4-pyridinyl, and X is S;

[0335] a compound of formula (Ia) wherein R₁ is 6-C₁, R₂ is Ph, m is 1,L is —CH₂—, R₃ is 4-pyridinyl, and X is S;

[0336] a compound of formula (Ia) wherein R₁ is 6,7-diF, R₂ is Ph, m is1, L is —CH₂—, R₃ is 4-pyridinyl, and X is S;

[0337] a compound of formula (Ia) wherein R₁ is 7-C₁, R₂ is Ph, m is 1,L is —CH₂—, R₃ is 4-pyridinyl, and X is S;

[0338] a compound of formula (Ia) wherein R₁ is 5-Cl, R₂ is Ph, m is 1,L is —CH₂—, R₃ is 4-pyridinyl, and X is S;

[0339] a compound of formula (Ia) wherein R₁ is 8-C₁, R₂ is Ph, m is 1,L is —CH₂—, R₃ is 4-pyridinyl, and X is S;

[0340] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-OMe)Ph,m is 1, L is —CH₂—, R₃ is 4-pyridinyl, and X is S;

[0341] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (3-OMe)Ph,m is 1, L is —CH₂—, R₃ is 4-pyridinyl, and X is S;

[0342] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (2-OMe)Ph,m is 1, L is —CH₂—, R₃ is 4-pyridinyl, and X is S;

[0343] a compound of formula (Ia) wherein R₁ is 6,7-diOMe, R₂ is—CH₂═CH₂, m is 1, L is —CH₂—, R₃ is 4-pyridinyl, and X is S;

[0344] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is cyclopropyl,m is 1, L is —CH₂—, R₃ is 4-pyridinyl, and X is S;

[0345] a compound of formula (Ia) wherein R₁ is 6-t-Bu, R₂ is(4-t-Bu)Ph, m is 1, L is —CH₂—, R₃ is 4-pyridinyl, and X is S;

[0346] a compound of formula (Ia) wherein R₁ is 6-CF₃, R₂ is (4-CF₃)Ph,m is 1, L is —CH₂—, R₃ is 4-pyridinyl, and X is S;

[0347] a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is 3-pyridinyl, and X is S;

[0348] a compound of formula (Ia) wherein R₁ is 8-F, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is 2-pyridinyl, and X is S;

[0349] a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis —CH₂CH₂—, R₃ is 4-pyridinyl, and X is S;

[0350] a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis —CH₂CH₂—, R₃ is 3-pyridinyl, and X is S;

[0351] a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis —CH₂CH₂—, R₃ is 2-pyridinyl, and X is S;

[0352] a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is (2-OMe-3-OH)-5-thienyl, and X is S;

[0353] a compound of formula (Ia) wherein R₁ is 6,7-diF, R₂ is Ph, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0354] a compound of formula (Ia) wherein R₁ is 8-C₁, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0355] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (2-OMe)Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0356] a compound of formula (Ia) wherein R₁ is 6,7-diOMe, R₂ is—CH₂═CH₂, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0357] a compound of formula (Ia) wherein R₁ is 6-t-Bu, R₂ is(4-t-Bu)Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X isO;

[0358] a compound of formula (Ia) wherein R₁ is 6-CF₃, R₂ is (4-CF₃)Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0359] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is (4-Cl)Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0360] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is (3-Cl)Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0361] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is (2-Cl)Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0362] a compound of formula (Ia) wherein R₁ is H, R₂ is (4-CF₃)Ph, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0363] a compound of formula (Ia) wherein R₁ is H, R₂ is (3-CF₃)Ph, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0364] a compound of formula (Ia) wherein R₁ is H, R₂ is (2-CF₃)Ph, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0365] a compound of formula (Ia) wherein R₁ is H, R₂ is (3-OMe-4-OH)Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0366] a compound of formula (Ia) wherein R₁ is H, R₂ is (3-OH-4-OMe)Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0367] a compound of formula (Ia) wherein R₁ is 6-OMe-7-OH, R₂ is Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compoundof formula (Ia) wherein R₁ is 6-OH-7-OMe, R₂ is Ph, m is 1, L is adirect bond, R₃ is 5-isoquinolinyl, and X is O;

[0368] a compound of formula (Ia) wherein R₁ is 6-Me, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0369] a compound of formula (Ia) wherein R₁ is 6-C(Me₂)CH₂Me, R₂ is Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0370] a compound of formula (Ia) wherein R₁ is 6-NO₂, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0371] a compound of formula (Ia) wherein R₁ is 6-OSO₃Me, R₂ is Ph, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0372] a compound of formula (Ia) wherein R₁ is 6-NHSO₂Ph, R₂ is Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0373] a compound of formula (Ia) wherein R₁ is 6-CO₂H, R₂ is Ph, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0374] a compound of formula (Ia) wherein R₁ is 6-C(O)NH₂, R₂ is Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0375] a compound of formula (Ia) wherein R₁ is 6-C(O)NMe₂, R₂ is Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0376] a compound of formula (Ia) wherein R₁ is 6-C(O)NHMe, R₂ is Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0377] a compound of formula (Ia) wherein R₁ is 6-CO₂Ph, R₂ is Ph, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0378] a compound of formula (Ia) wherein R₁ is 6-cyclohexyl, R₂ is Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0379] a compound of formula (Ia) wherein R₁ is 6-Ph, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0380] a compound of formula (Ia) wherein R₁ is6-NHC(O)(CH₂)₄—CH═CH—CH(Me)₂, R₂ is Ph, m is 1, L is a direct bond, R₃is 5-isoquinolinyl, and X is O;

[0381] a compound of formula (Ia) wherein R₁ is H, R₂ is 2-pyridinyl, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0382] a compound of formula (Ia) wherein R₁ is H, R₂ is 3-pyridinyl, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0383] a compound of formula (Ia) wherein R₁ is H, R₂ is 4-pyridinyl, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0384] a compound of formula (Ia) wherein R₁ is H, R₂ is 3-thienyl, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0385] a compound of formula (Ia) wherein R₁ is H, R₂ is 3-furyl, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0386] a compound of formula (Ia) wherein R₁ is H, R₂ is 2-furyl, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0387] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 3-hydroxynaphth-8-yl, and X is O;

[0388] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 1-hydroxynaphth-8-yl, and X is O;

[0389] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 4-hydroxynaphth-8-yl, and X is O;

[0390] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 5-hydroxynaphth-8-yl, and X is O;

[0391] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 3-chloro-2-hydroxynaphth-8-yl, and X is O;

[0392] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 2,3-dihydroxynaphth-8-yl, and X is O;

[0393] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 5-quinolinyl, and X is O;

[0394] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 5-cinnolinyl, and X is O;

[0395] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 3-Me-5-quinolinyl, and X is O;

[0396] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 4-(1,8-naphthyridinyl), and X is O;

[0397] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 5-quinazolinyl, and X is O;

[0398] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 2-OH-5-quinolinyl, and X is O;

[0399] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 3-OH-5-quinolinyl, and X is O;

[0400] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 3-F-5-quinolinyl, and X is O;

[0401] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 3-Cl-5-quinolinyl, and X is O;

[0402] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 2-OH-3-Cl-5-quinolinyl, and X is O;

[0403] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is —CH₂═CH₂, mis 1, L is a direct bond, R₃ is 5-quinolinyl, and X is O;

[0404] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is —CH₂CH₃, m is1, L is a direct bond, R₃ is 5-quinolinyl, and X is O;

[0405] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 8-Cl-5-quinolinyl, and X is O;

[0406] a compound of formula (Ia) wherein R₁ is H, R₂ is 2-naphthyl, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0407] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 1,3-diMe-5-isoquinolinyl, and X is O;

[0408] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 8-Cl-5-isoquinolinyl, and X is O;

[0409] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 1,3-diMe-8-Cl-5-isoquinolinyl, and X is O;

[0410] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is 5-isoquinolinyl, and X is O;

[0411] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 3-quinolinyl, and X is O;

[0412] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 3-quinolinyl, and X is O;

[0413] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 3-quinolinyl, and X is O;

[0414] a compound of formula (Ia) wherein R₁ is 6-OH-7-OMe, R₂ is Ph, mis 1, L is a direct bond, R₃ is 3-quinolinyl, and X is O;

[0415] a compound of formula (Ia) wherein R₁ is 6,7-diOH, R₂ is Ph, m is1, L is a direct bond, R₃ is 3-quinolinyl, and X is O;

[0416] a compound of formula (Ia) wherein R₁ is 6-OMe-7-OH, R₂ is Ph, mis 1, L is a direct bond, R₃ is 3-quinolinyl, and X is O;

[0417] a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 3-quinolinyl, and X is O;

[0418] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 1-Cl-5-isoquinolinyl, and X is O;

[0419] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 1-Me-5-isoquinolinyl, and X is O;

[0420] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 3-Me-5-isoquinolinyl, and X is O;

[0421] a compound of formula (Ia) wherein R₁ is 6-Br, R₂ is Ph, m is 1,L is a direct bond, R₃ is 8-isoquinolinyl, and X is O;

[0422] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is 2-furyl, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0423] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0424] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 4-Cl-5-isoquinolinyl, and X is O;

[0425] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 5-isoquinolinyl-N-oxide, and X is O;

[0426] a compound of formula (Ia) wherein R₁ is 6-C₁, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0427] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is 3-furanyl, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0428] a compound of formula (Ia) wherein R₁ is 6-OCH₃, R₂ is 3-thienyl,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O

[0429] a compound of formula (Ia) wherein R₁ is 6-OCH₃, R₂ is 2,4 di-FPh, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0430] a compound of formula (Ia) wherein R₁ is 6-OCH₃, R₂ is 2,4 di-FPh, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0431] a compound of formula (Ia) wherein R₁ is 6-OCH₃, R₂ is Ph, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0432] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0433] a compound of formula (Ia) wherein R₁ is 6-C₁, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0434] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 5-isoquinolinyl-N-oxide, and X is O;

[0435] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 4-Cl-5-isoquinolinyl, and X is O;

[0436] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 4-Cl-5-isoquinolinyl, and X is O;

[0437] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 3-methyl-5-isoquinolinyl, and X is O;

[0438] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 1-methyl-5-isoquinolinyl, and X is O;

[0439] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 1-Cl-5-isoquinolinyl, and X is O;

[0440] a compound of formula (Ia) wherein R₁ is 6-C₁, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl-N-oxide, and X is O;

[0441] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is 4-CF₃ Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0442] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 1,3-diCl-5-isoquinolinyl, and X is O;

[0443] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 1,3-diCl-5-isoquinolinyl, and X is O;

[0444] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 8-Cl-5-isoquinolinyl, and X is O;

[0445] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 1-piperidinyl-5-isoquinolinyl, and X is O;

[0446] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 1-OCH₃-5-isoquinolinyl, and X is O;

[0447] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 1-F-5-isoquinolinyl, and X is O;

[0448] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 1-N,N-dimethyl-5-isoquinolinyl, and X is O;

[0449] a compound of formula (Ia) wherein R₁ is 6-C₁, R₂ is nil, m isnil, R₃ is 1-CH₃-5-isoquinolinyl, and X is O;

[0450] a compound of formula (Ia) wherein R₁ is 6-C₁, R₂ is nil, m isnil, R₃ is 1-Cl-5-isoquinolinyl, and X is O;

[0451] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is 3-CF₃ Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0452] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is 3-CF₃ Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl-N-oxide, and X is O;

[0453] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is 3-CF₃ Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl-N-oxide, and X is O;

[0454] a compound of formula (Ia) wherein R₁ is 6-F, R₂ isspiro-2-indanyl, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0455] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is 4-Cl, 3-CF₃Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O; and

[0456] a compound of formula (Ia) wherein R₁ is 6-C₁, R₂ is Ph, m is 1,L is a direct bond, R₃ is 1-CH₃-5-isoquinolinyl, and X is O.

[0457] Preferred compounds of Formula (Ia) are selected from the groupconsisting of:

[0458] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0459] a compound of formula (Ia) wherein R₁ is H, R₂ is 3-Pyridinyl, mis 1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0460] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is O;

[0461] a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0462] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is (3,4-diOMe)Ph, and X is S;

[0463] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0464] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is a direct bond, R₃ is 8-(2-naphtholyl), and X is O;

[0465] a compound of formula (Ia) wherein R₁ is H, R₂ is H, m is 0, L isa direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0466] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is H, m is 0, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0467] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0468] a compound of formula (Ia) wherein R₁ is 6-Br, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0469] a compound of formula (Ia) wherein R₁ is 6,7-diOMe, R₂ is Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0470] a compound of formula (Ia) wherein R₁ is 7-C₁, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0471] a compound of formula (Ia) wherein R₁ is 5-C₁, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0472] a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0473] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (3-Cl)Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0474] a compound of formula (Ia) wherein R₁ is 6,7-diOMe, R₂ is Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0475] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (2-Cl)Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0476] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-Cl)Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0477] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is H, m is 0,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0478] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (2-CF₃)Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0479] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (3-CF₃)Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0480] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-CF₃)Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0481] a compound of formula (Ia) wherein R₁ is H, R₂ is —CH═CH₂, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0482] a compound of formula (Ia) wherein R₁ is 6-Br, R₂ is H, m is 0, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0483] a compound of formula (Ia) wherein R₁ is 6-C₁, R₂ is H, m is 0, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0484] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is 5-isoquinolinyl, and X is O;

[0485] a compound of formula (Ia) wherein R₁ is 7-C₁, R₂ is H, m is 0, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0486] a compound of formula (Ia) wherein R₁ is 8-C₁, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0487] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-CN)Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0488] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-Br)Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0489] a compound of formula (Ia) wherein R₁ is 6,7-diF, R₂ is Ph, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0490] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is —CH═CH₂, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0491] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is —CH═CH₂, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0492] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-OMe)Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0493] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (2-OMe)Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0494] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is 2-Thienyl, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O.

[0495] More preferred compounds of Formula (Ia) are selected from thegroup consisting of:

[0496] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0497] a compound of formula (Ia) wherein R₁ is 6-Br, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0498] a compound of formula (Ia) wherein R₁ is 5-C₁, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0499] a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0500] a compound of formula (Ia) wherein R₁ is 6-Br, R₂ is H, m is 0, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0501] a compound of formula (Ia) wherein R₁ is 6-C₁, R₂ is H, m is 0, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0502] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is 5-isoquinolinyl, and X is O;

[0503] a compound of formula (Ia) wherein R₁ is 7-C₁, R₂ is H, m is 0, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0504] a compound of formula (Ta) wherein R₁ is 6,7-diF, R₂ is Ph, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0505] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is —CH═CH₂, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0506] a compound of formula (Ia) wherein R₁ is 6-F, R₂ is 2-Thienyl, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O.

[0507] Still other more preferred compounds of Formula (Ia) are selectedfrom the group consisting of:

[0508] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1,L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;

[0509] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (3-Cl)Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0510] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (2-Cl)Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0511] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (2-CF₃)Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0512] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (3-CF₃)Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0513] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-CF₃)Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0514] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-Br)Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0515] a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-OMe)Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;

[0516] The compounds of the present invention may also be present in theform of pharmaceutically acceptable salts. For use in medicine, thesalts of the compounds of this invention refer to non-toxic“pharmaceutically acceptable salts” (Ref. International J. Pharm., 1986,33, 201-217; J. Pharm.Sci., 1997 (January), 66, 1, 1). Other salts wellknown to those in the art may, however, be useful in the preparation ofcompounds according to this invention or of their pharmaceuticallyacceptable salts. Representative organic or inorganic acids include, butare not limited to, hydrochloric, hydrobromic, hydriodic, perchloric,sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic,succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic,methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representative organicor inorganic bases include, but are not limited to, basic or cationicsalts such as benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium and zinc.

[0517] The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

[0518] Where the compounds according to this invention have at least onechiral center, they may accordingly exist as enantiomers. Where thecompounds possess two or more chiral centers, they may additionallyexist as diastereomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention. Furthermore, some of the crystalline forms for the compoundsmay exist as polymorphs and as such are intended to be included in thepresent invention. In addition, some of the compounds may form solvateswith water (i.e., hydrates) or common organic solvents, and suchsolvates are also intended to be encompassed within the scope of thisinvention.

[0519] Where the processes for the preparation of the compoundsaccording to the invention give rise to mixture of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

[0520] During any of the processes for preparation of the compounds ofthe present invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

[0521] Even though the compounds of the present invention (includingtheir pharmaceutically, acceptable salts and pharmaceutically acceptablesolvates) can be administered alone, they will generally be administeredin admixture with a pharmaceutical carrier, excipient or diluentselected with regard to the intended route of administration andstandard pharmaceutical or veterinary practice. Thus, the present invention is directed to pharmaceutical and veterinary compositionscomprising compounds of Formula (I) and one or more pharmaceuticallyacceptable carriers, excipients or diluents.

[0522] By way of example, in the pharmaceutical and veterinarycompositions of the present invention, the compounds of the presentinvention may be admixed with any suitable binder(s), lubricant(s),suspending agent(s), coating agent(s), and/or solubilising agent(s).

[0523] Tablets or capsules of the compounds may be administered singlyor, two or more at a time, as appropriate. It is also possible toadminister the compounds in sustained release formulations.

[0524] Alternatively, the compounds of the general Formula (I) can beadministered by inhalation or in the form of a suppository or pessary,or they may be applied topically in the form of a lotion, solution,cream, ointment or dusting powder. An alternative means of transdermaladministration is by use of a skin patch. For example, they can beincorporated into a cream consisting of an aqueous emulsion ofpolyethylene glycols or liquid paraffin. They can also be incorporated,at a concentration of between 1 and 10% by weight, into an ointmentconsisting of a white wax or white soft paraffin base together with suchstabilisers and preservatives as may be required.

[0525] For some applications, preferably the compositions areadministered orally in the form of tablets containing excipients such asstarch or lactose, or in capsules or ovules either alone or in admixturewith excipients, or in the form of elixirs, solutions or suspensionscontaining flavouring or coloring agents.

[0526] The compositions (as well as the compounds alone) can also beinjected parenterally, for example intracavernosally, intravenously,intramuscularly or subcutaneously. In this case, the compositions willcomprise a suitable carrier or diluent.

[0527] For parenteral administration, the compositions are best used inthe form of a sterile aqueous solution which may contain othersubstances, for example enough salts or monosaccharides to make thesolution isotonic with blood.

[0528] For buccal or sublingual administration the compositions may beadministered in the form of tablets or lozenges which can be formulatedin a conventional manner.

[0529] By way of further example, pharmaceutical and veterinarycompositions containing one or more of the compounds of the inventiondescribed herein as the active ingredient can be prepared by intimatelymixing the compound or compounds with a pharmaceutical carrier accordingto conventional pharmaceutical compounding techniques. The carrier maytake a wide variety of forms depending upon the desired route ofadministration (e.g., oral, parenteral). Thus for liquid oralpreparations such as suspensions, elixirs and solutions, suitablecarriers and additives include water, glycols, oils, alcohols, flavoringagents, preservatives, stabilizers, coloring agents and the like; forsolid oral preparations, such as powders, capsules and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like. Solidoral preparations may also be coated with substances such as sugars orbe enteric-coated so as to modulate the major site of absorption. Forparenteral administration, the carrier will usually consist of sterilewater and other ingredients may be added to increase solubility orpreservation. Injectable suspensions or solutions may also be preparedutilizing aqueous carriers along with appropriate additives.

[0530] Advantageously, compounds of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three or four times daily.Furthermore, compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal skin patches well known to those skilled in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

[0531] A therapeutically effective amount for use of the instantcompounds or a pharmaceutical composition thereof comprises a dose rangeof from about 0.001 mg to about 1,000 mg, in particular from about 0.1mg to about 500 mg or, more particularly from about 1 mg to about 250 mgof active ingredient per day for an average (70 kg) human.

[0532] For oral administration, a pharmaceutical composition ispreferably provided in the form of tablets containing, 0.01, 0.05, 0.1,0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the subject to be treated.

[0533] It is also apparent to one skilled in the art that thetherapeutically effective dose for active compounds of the invention ora pharmaceutical composition thereof will vary according to the desiredeffect. Therefore, optimal dosages to be administered may be readilydetermined and will vary with the particular compound used, the mode ofadministration, the strength of the preparation, and the advancement ofthe disease condition. In addition, factors associated with theparticular subject being treated, including subject age, weight, dietand time of administration, will result in the need to adjust the doseto an appropriate therapeutic level. The above dosages are thusexemplary of the average case. There can, of course, be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

[0534] Compounds of this invention may be administered in any of theforegoing compositions and dosage regimens or by means of thosecompositions and dosage regimens established in the art whenever use ofthe compounds of the invention as vanilloid receptor modulators isrequired for a subject in need thereof.

[0535] The invention also provides a pharmaceutical or veterinary packor kit comprising one or more containers filled with one or more of theingredients of the pharmaceutical and veterinary compositions of theinvention. Optionally associated with such container(s) can be a noticein the form prescribed by a governmental agency regulating themanufacture, use or sale of pharmaceuticals or biological products,which notice reflects approval by the agency of manufacture, use or salefor human administration.

[0536] As modulators of the vanilloid VR1 ion channel, the compounds ofFormula (I) are useful in methods for treating or preventing a diseaseor condition in a mammal which disease or condition is affected by themodulation of one or more vanilloid receptors. Such methods comprisesadministering to a mammal in need of such treatment or prevention atherapeutically effective amount of a compound, salt or solvate ofFormula (I). In particular, the compounds of Formula (I) are useful forin methods for preventing or treating a chronic- or acute-pain causingdiseases or conditions and pulmonary dysfunction, and more particulalry,in treating diseases or conditions that cause inflammatory pain, burningpain, itch or urinary incontinence, and chronic obstructive pulmonarydisease.

[0537] By way of example only, the compounds of Formula (I) are usefulfor treating diseases and conditions selected from the group consistingof osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine,headache, toothache, burn, sunburn, snake bite (in particular, venomoussnake bite), spider bite, insect sting, neurogenic bladder, benignprostatic hypertrophy, interstitial cystitis, urinary tract infection,cough, asthma, chronic obstructive pulmonary disease, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, anxiety, panic disorders,pharyngitis, mucositis, enteritis, cellulites, peripheral neuropathy,bilateral peripheral neuropathy, diabetic neuropathy, postherpeticneuralgia, trigeminal neuralgia, causalgia, sciatic neuritis, mandibularjoint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantomlimb pain, bony fractures, post-operative ileus, irritable bowelsyndrome, inflammatoryinflammatory bowel diseases such as Crohn'sDisease and ulcerative colitis, cholecystitis, pancreatitis,postmastectomy pain syndrome, oral neuropathic pain, Charcot's pain,reflex sympathetic dystrophy, Guillain-Barre syndrome, meralgiaparesthetica, burning-mouth syndrome, optic neuritis, postfebrileneuritis, migrating neuritis, segmental neuritis, Gombault's neuritis,neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculateneuralgia, glossopharyngial neuralgia, migrainous neuralgia, idiopathicneuralgia, intercostals neuralgia, mammary neuralgia, Morton'sneuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia,Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia,vidian neuralgia, sinus headache, tension headache, labor, childbirth,intestinal gas, menstruation, cancer, and trauma.

[0538] While the present invention comprises compositions comprising oneor more of the compounds of Formula (I), the present invention alsocomprises compositoins comprising intermediates used in the manufactureof compounds of Formula (I).

General Synthetic Methods

[0539] Representative compounds of the present invention can besynthesized in accordance with the general synthetic methods describedbelow and are illustrated in the schemes that follows. Since the schemesare an illustration, the invention should not be construed as beinglimited by the chemical reactions and conditions expressed. Thepreparation of the various starting materials used in the schemes iswell within the skill of persons versed in the art.

[0540] The ureas of formula (I) that comprise this invention aresynthesized using several distinct chemical methods. The generaltransformations for constructing β-aminotetralin-derived ureas involve:

[0541] Preparation of suitably substituted β-aminotetralin, which isdescribed in the general schemes below. Tetralone starting materialswere either purchased from commercial sources or were prepared using themethod reported by Sims (Sims, J. J. et. al. Tetrahedron Lett. 1971,951). Specifically, substituted phenylacetic acids were separatelyreacted with ethylene gas and a Lewis Acid such as aluminum trichlorideto afford the desired corresponding β-tetralone.

[0542] An appropriately substituted β-tetralone (II) is reacted with anaryl or heteroaryl aldehyde in the presence of a base such aspiperidine, in an inert halohydrocarbon, ethereal or hydrocarbonsolvent, such as benzene, from ambient temperature to reflux, to affordthe corresponding α-benzylidenyl-β-tetralone orα-heteroarylmethylidenyl-β-tetralone (III). The β-tetralone (III) isdissolved in an inert hydrocarbon, ethereal, ester or alcohol solvent,such as methanol, and reacted with hydrogen gas at a pressure fromambient pressure to 100 p.s.i. in the presence of a suitable catalystsuch as palladium on carbon. The reaction is performed at a temperaturefrom ambient temperature to reflux, to yield the desiredα-substituted-β-tetralone (IV) (Scheme 1).

[0543] An alternative method for the preparation ofα-substitutedβ-tetralones (IV) involves the reaction of an appropriatelysubstituted β-tetralone (II) with a base such as pyrrolidine in an inerthalohydrocarbon solvent such as dichloromethane or hydrocarbon solventsuch as benzene, under Dean-Stark conditions (removal of water) or in analcohol solvent such as methanol, from ambient temperature to reflux, toafford enamine (V). Alkylation of enamine (V) is accomplished byreaction with a benzylic, heterocyclicalkanyl or an allylic halide in aninert solvent such as acetonitrile, at a temperature from ambienttemperature to reflux, to afford the α-substituted-β-iminium salt (VI).Hydrolysis of the salt (VI) to produce the desiredα-substituted-β-tetralone product (IV) is accomplished by reaction of(VI) with water and an inorganic or organic acid such as hydrochloric orglacial acetic acid in an inert hydrocarbon, ethereal, alcohol orhalohydrocarbon solvent, or a mixture thereof, such as methanol anddichloromethane (Scheme 1).

[0544] The α-substituted-β-tetralones (IV) are converted to thecorresponding aminotetralins via reaction with an ammonium salt such asammonium acetate in the presence of a reducing agent such as sodiumcyanoborohydride, for example, in an inert halohydrocarbon, hydrocarbon,ethereal or alcohol solvent such as methanol to produce thecis-aminotetralin (VII). In some cases, the trans-aminotetralin (VIII)is also formed as a minor product; both sets of diastereomers are partof this invention. The aminotetralins (VII) can also be isolated as acidaddition salts by treatment with an organic or an inorganic acid, suchas trifluoroacetic acid or hydrochloric acid, for example (Scheme 2).

[0545] Compounds in which m=0 are prepared from an appropriatelysubstituted aminotetralin (VII; m=0) starting from 1-tetralones usingthe synthetic sequence shown in Scheme 2a.

[0546] Aminotetralin (VII) can be used in subsequent reactions as thecorresponding free base or as an acid addition salt. The use of acidaddition salts requires an additive, such as an organic base liketriethylamine or an inorganic base such as hydroxide, to neutralize theacid and liberate the reactive nucleophilic amine center. This commonpractice is well known to those skilled in the art.

[0547] Aminotetralin VII is reacted with isocyanate or isothiocyanate,in an appropriate inert solvent, with or without an added base, to formureas (IX) or thioureas (X), shown in Scheme 3.

[0548] In addition to isocyanates and isothiocyanates, othercarbamylating or thiocarbamylating agents may be used and this is wellknown to those skilled in the art. Thus an appropriate amine, such as anaminoisoquinoline, aminonaphthol or aminoquinoline, is reacted with achloroformate, such as phenyl chloroformate in an inert solvent, with orwithout added base, to afford the corresponding phenylcarbamates.Separately these carbamates are reacted with aminotetralin (VII) in apolar solvent such as dimethylsulfoxide, with or without added base,from room temperature to approximately 150 C, to produce theaminotetralin-derived ureas (IX) (Scheme 4).

[0549] The use of chlorothionoformates in the scheme above produces theanalogous aminotetralin-derived thioureas (X).

[0550] Isocyanates and isothiocyanates are also prepared by reacting anamine with phosgene or thiophosgene in the presence of a base.Benzylamines such as 4-alkanyloxy-3-methoxybenzylamine is reacted withthiophosgene or a thiophosgene equivalent, in the presence of a base,such as an organic amine, to produce the corresponding thiocyanate.Subsequent reaction with aminotetralin (VII) produces the correspondingaminotetralin-derived homovanillic thioureas (Scheme 5). Protectinggroup manipulations may be used to mask and subsequently liberate thephenolic OH group and this practice is well known to those skilled inthe art.

[0551] The use of (heteroaryl)alkanylamines, such as pyridylmethylamine,produces the corresponding aminotetralin-derived ureas in whichR₃=heteroaryl (Scheme 6). Thiocarbamylation with aminotetralin, asdescribed above, gives the analogous thioureas.

[0552] Aminotetralin-derived ureas and thioureas with linking groups (L)of varying length are produced via homologation of aryl- orheteroaryl-carboxaldehydes or carboxylic acids. This practice is wellknown in the literature and encompasses a wide variety of chemicaltransformations, several of which are described below to illustrate thestrategy but are not intended to be inclusive.

[0553] Isoquinoline is reacted with N-(hydroxymethyl)trifluoroacetamidein acid followed by reduction to afford isoquinolin-5-yl-methylamine.Carbamylation using aminotetralin as described above, producesaminotetralin-derived ureas in which L=CH₂ (methylene) (Scheme 7).

[0554] Aminonaphthalene is subjected to a Sandmeyer reaction, namelydiazotization followed by reaction with copper cyanide at hightemperature to produce the cyanonaphthalene. Reduction affordsnaphthalen-2-yl-methylamine which is subjected to carbamylation usingaminotetralin (VII), as described above, to produceaminotetralin-derived urea in which L=CH₂ (methylene) (Scheme 8).

[0555] Reaction of aryl- and heteroaryl-carboxaldehydes withtoluenesulfonyl methylisocyanide in the presence of base, withsubsequent hydrolysis affords the corresponding homologated nitrile.Reduction produces the homologated amine which is subjected tocarbamylation with aminotetralin as described above to yieldaminotetralin-derived ureas in which L=CH₂CH₂ (Scheme 9).

[0556] Heteroaryl- and aryl-carboxaldehydes are modified using Wittigconditions to give the α,β-unsaturated nitrile which is reduced to theamine and subsequent carbamylated as described above to yieldaminotetralin-derived ureas in which L=CH₂CH₂ CH₂ (Scheme 10).

[0557] Homologation of heteroaryl- and aryl-carboxylic acids is alsoaccomplished using chemistry known as the Arndt-Eistert synthesis, aprocedure that converts carboxylic acids to the next higher homologusing a three step synthesis. In the first transformation, thecarboxylic acid starting material is converted to its acyl chloride,using thionyl chloride, oxalyl chloride or another appropriatechlorinating agent. In the second step, the acyl chloride is convertedto a diazoketone via reaction with diazomethane or a suitableequivalent. In the final transformation, the diazoketone is oxidized tothe homologous acid using an oxidant such as silver oxide. Thecarboxylic acid group is then converted to an isocyanate through theintermediacy of the acyl azide (Curtius rearrangement) which is carriedon to aminotetralin-derived ureas and thioureas using the chemistrydescribed above. Alternatively, the carboxylic acid is reacted withhydrazoic acid (or equivalent) under acid catalysis followed by thermaldecomposition to the amine (Schmidt reaction), which is carried on toaminotetralin-derived ureas and thioureas using the chemistry describedabove.

[0558] This chemistry and related variations are well known to thoseskilled in the art.

[0559] Protecting group manipulations may be needed at various stages ofthe syntheses depending upon substituents and functional groups that arepresent on the reactants.

[0560] It is generally preferred that the respective product of eachprocess step be separated from other components of the reaction mixtureand subjected to purification before its use as a starting material in asubsequent step Separation techniques typically include evaporation,extraction, precipitation and filtration. Purification techniquestypically include column chromatography (Still, W. C. et. al., J. Org.Chem. 1978, 43, 2921), thin-layer chromatography, crystallization anddistillation. The structures of the final products, intermediates andstarting materials are confirmed by spectroscopic, spectrometric andanalytical methods including nuclear magnetic resonance (NMR), massspectrometry (MS) and liquid chromatography (HPLC). In the descriptionsfor the preparation of compounds of this invention, ethyl ether,tetrahydrofuran and dioxane are common examples of an ethereal solvent;benzene, toluene, hexanes and cyclohexane are typical hydrocarbonsolvents and dichloromethane and dichloroethane are representativehalogenhydrocarbon solvents. In those cases wherein the product isisolated as the acid addition salt the free base may be obtained bytechniques known to those skilled in the art. In those cases in whichthe product is isolated as an acid addition salt, the salt may containone or more equivalents of the acid.

[0561] Representative compounds of the present invention can besynthesized in accordance with the general synthetic methods describedabove and are illustrated more particularly in the schemes that follow.Since the schemes are illustrations, the invention should not beconstrued as being limited by the chemical reactions and conditionsexpressed. The preparation of the various starting materials used in theschemes is well within the skill of persons versed in the art.

EXAMPLE 11-(1-Benzyl-6-methoxy-1,2,3,4-tetrahydronaphthalene-2-yl)-3-isoquinolin-5-yl-ureaCompound 33

[0562]

[0563] Isoquinolin-5-yl-carbamic acid phenyl ester 1-1 (0.004 mole, 1.06g) was dissolved in 15 mL of dimethylsulfoxide. Diisopropylethyl amine(0.0044 mole, 0.57 g, 0.8 mL) was added followed by addition of1-benzyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydrochloride1-2 (0.0044 mole, 1.33 g). The reaction mixture was stirred at roomtemperature for 16 hours. The reaction mixture was then poured into 50mL of water containing 10 mL of 1 N sodium hydroxide. The precipitatedsolid was collected by filtration. This solid was chromatographed onsilica gel eluting with methylene chloride, 3% methanol. Subsequentlythe product was further purified by recrystallization from ethylacetate. The title compound 33(1-(1-benzyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-isoquinolin-5-yl-urea)was obtained as an off-white solid (1.05 g, 0.0024 mole). MS (MH+): 438;¹H NMR (CDCl₃): δ 1.7-1.8 (m, 2H), 2.6-2.9 (m, 4H), 3.6 (s, 3H), 4.1(m,1H), 5.8 (d,1H), 6.4-6.4 (m, 3H), 6.95 (d, 2H), 7.1 (m, 3H), 7.3 (t,1H), 7.4-7.5 (m, 2H), 8.2 (d, 2H), 9.0 (s, 1H).

EXAMPLE 21-(1-Benzyl-6-fluoro-1,2,3,4-tetrahydronaphthalene-2-yl)-3-isoquinolin-5-yl-ureaCompound 38

[0564]

[0565] Isoquinolin-5-yl-carbamic acid phenyl ester 2-1 (0.005 mole, 1.32g) was dissolved in 15 mL of DMSO (dimethylsulfoxide) followed by theaddition of the aminotetralin 2-2,1-benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamine (0.0044 mole,1.12 g). The reaction mixture was then stirred at room temperature for16 hours. The reaction mixture was poured into 50 mL of water containing10 mL of 1 N NaOH (sodium hydroxide). The precipitated solid wascollected by filtration. This solid was chromatographed on silica geleluting with methylene chloride, 3% methanol. Subsequently the productwas further purified by recrystallization from ethyl acetate. The titlecompound 38,(1-(1-benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-isoquinolin-5-yl-urea)was obtained as an off-white solid (1.25 g, 0.00295 mole). MS (MH⁺):426; ¹H NMR (MeOH): δ 1.35 (m, 1H), 1.9 (m, 1H), 2.1-2.2 (m, 1H),2.9-3.1 (m, 4H) 3.45 (m, 1H), 4.1-4.2 (m, 1H), 6.7 (t, 1H), 6.8-6.9 (m,2H), 7.1-7.3 (m, 5H), 7.85 (t, 1H), 8.1 (d, 1H), 8.25 (d, 1H), 8.35 (d,1H), 8.6 (d, 1H).

EXAMPLE 31-(1-cyclopropylmethyl-6-fluoro-1,2,3,4-tetrahydronaphthalene-2-yl)-3-isoquinolin-5-yl-ureaCompound 71

[0566]1-Cyclopropylmethyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylaminehydrochloride (127 mg, 0.49 mmol), isoquinolin-5-yl-carbamic acid phenylester (150 mg, 0.49 mmol), and diisopropylethylamine (193 mg, 1.47 mmol)were combined and stirred at ambient temperature in DMSO (3 mL)overnight. The product was purified by directly injecting the crudereaction onto a reverse phase prep-HPLC (10-90% water:acetonitrilegradient). The appropriate fractions were lyophilized to yield1-(1-cyclopropylmethyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-isoquinolin-5-yl-urea71 (68 mg, 0.14 mmol). MS (MH⁺) 390; ¹H NMR (CD₃OD) δ 0.08-0.87 (m, 2H),1.60-1.65 (m, 2H), 2.03 (m, 1H), 2.97 (m, 2H), 3.14 (m, 1H), 4.36 (m,1H), 6.87 (m, 2H), 7.27 (m, 1H), 7.93 (t, 1H, J=2.6 Hz), 8.14 (d, 1H,J=2.7 Hz), 8.32 (d, 1H, J=2.2 Hz), 8.47 (d, 1H, J=2.6 Hz), 8.53 (d, 1H,J=2.2 Hz), 9.63 (s, 1H). HPLC R_(t)=3.63 min (10-90% water:acetonitrilegradient, 100% pure).

EXAMPLE 41-(1-Benzyl-6-fluoro-1,2,3,4-tetrahydronaphthalene-2-yl)-3-isoquinolin-5-ylmethyl-ureaCompound 60

[0567]

[0568] Isoquinoline 4-1 (0.01 mole, 1.29 g) was dissolved in 50 mL ofconcentrated H₂SO₄ (sulfuric acid) which had been cooled to 0° C. in anice-water bath. The N-hydroxymethyl trifluoroacetamide was then added inportions. The reaction mixture was stirred at 0° C. for 15 minutes andthen allowed to warm to room temperature and stirred for 16 hours. Theclear light brown reaction mixture was poured onto 200 g of ice thenNH₄OH (ammonium hydroxide) was added until the reaction mixture wasbasic to pH paper. The aqueous mixture was extracted with 100 mL ofCH₂Cl₂ (methylene chloride). The organic layer was separated and washedwith 2×100 mL of brine, dried over Na₂SO₄ (sodium sulfate) andevaporated in vacuo. The residue was chromatographed on silica geleluting with 60/40 hexane/ethyl acetate to yield the trifluoroacetamide4-2 product as a white crystalline solid (0.008 mole, 2.03 g). MS (MH+):255; ¹H NMR (CDCl₃): δ 5.0 (s, 2H), 7.6 (t, 1H), 7.8 (d, 1H), 7.95 (d,1H), 8.1 (d, 1H), 8.5 (d, 1H), 9.2 (s, 1H).

[0569] The trifluoroacetamide 4-2 from step A (0.006 mole, 1.53 g) wasdissolved in 50 mL of methanol. Sodium borohydride (0.02 mole, 0.8 g)was then added and the reaction mixture was stirred at room temperaturefor 2 hours. Thin layer chromatography (silica gel, 50/50 hexane/ethylacetate) showed the reaction to be nearly complete. An additional amountof sodium borohydride was added (0.01 mole, 0.4 g) and stirring wascontinued for another 1 hour. The reaction mixture was evaporated invacuo. The residue was taken up in 50 mL of CH₂Cl₂ and then washed with2×50 mL of brine, dried over Na₂SO₄ and evaporated in vacuo to yield theamine product 4-3 as a clear oil (0.005 mole, 0.79 g). MS (MH⁺): 159; ¹HNMR (CDCl₃): δ 4.3 (s, 2H), 7.5 (t, 1H), 7.7 (d, 1H), 7.8 (d, 1H), 7.9(d, 1H), 8.5 (d, 1H), 9.2 (s, 1H).

[0570] The amine 4-3 from step B (0.005 mole, 0.79 g) was dissolved in20 mL of tetrahydrofuran (THF). Pyridine (0.0055 mole, 0.44 g, 0.44 mL)was added followed by the careful addition of phenylchloroformate(0.0055 mole, 0.86 g, 0.69 mL). The reaction mixture immediately turnedyellow and turbid. Stirring at room temperature was continued for 2hours. The reaction mixture was evaporated in vacuo. The residue wastaken up in 50 mL of dichloromethane, washed with 2×100 mL saturatedsodium bicarbonate then 2×100 mL of water. The organic layer was driedover sodium sulfate and evaporated in vacuo to give a thick slightlyyellow oil. This oil was triturated with diethylether and then treatedwith 1M HCl/diethylether to give the carbamate hydrochloride product 4-4as an off-white solid. MS (MH+): 279; ¹H NMR (MeOH): δ 4.6 (s, 2H), 6.8(m, 1H), 7.1-7.4 (m, 4H), 7.9 (t, 2H), 8.1 (d, 1H), 8.5 (d, 1H), 8.8 (d,1H), 9.8 (s, 1H).

[0571] The carbamate hydrochloride 4-4 from step C (0.0005 mole, 0.139g) was dissolved in 2 mL of dimethylsulfoxide. Diisopropylethyl amine(0.0011 mole, 0.142 g, 0.19 mL) was added followed by addition of1-benzyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydrochloride(0.00055 mole, 0.297 g). The reaction mixture was stirred at roomtemperature for 4 hours. The reaction mixture was then poured into 20 mLof water containing 5 mL of 1 N sodium hydroxide and stirred at roomtemperature for 15 minutes. The precipitated solid was collected byfiltration. This cream colored powder was recrystallized from ethylacetate/hexane to afford the title product 60,1-(1-benzyl-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-isoquinolin-5-yl-methylurea as a white chalky powder (0.000015 mole, 0.065 g). MS (MH+): 440;¹H NMR (CDCl₃): δ 1.8-2.0 (m, 2H), 2.8-3.0 (m, 4H), 4.1 (m 1H), 4.35 (d,1H), 4.5 (m, 1H), 4.8 (d, 2H), 6.6-6.8 (m, 4H), 7.1-7.3 (m, 4H), 7.5 (t,1H), 7.6 (d, 1H), 7.8 (d 1H), 7.9 (d, 1H), 8.6 (d, 1H), 9.2 (s, 1H).

EXAMPLE 51-(1-Benzyl-6-fluoro-1,2,3,4-tetrahydronaphthalene-2-yl)-3-(7-hydroxy-naphthalen-1-yl)-ureaCompound 67

[0572] 8-Amino-naphthalen-2-ol (74 mg, 0.46 mmol) was added to asolution of1-benzyl-2-isocyanato-6-methoxy-1,2,3,4-tetrahydro-naphthalene (136 mg,0.46 mmol) in acetonitrile (2 mL). The reaction was microwaved for 5 minat 100° C. The solvent was stripped off and the residue chromatographedon a silica column using chloroform as eluant to yield title compound 68(95 mg, 45%) MS (MH⁺) 453; ¹H NMR (CD₃OD) δ 1.87 (m, 1H), 2.02 (m, 1H),2.89-2.93 (m, 4H), 3.38 (m, 1H), 3.73 (s, 3H), 4.05 (m, 1H), 6.52 (d,1H, J=3 Hz), 6.65 (m, 2H), 7.09 (d, 3H, J=2.4 Hz), 7.14 (d, 1H, J=2.2Hz), 7.21 (d, 2H, J=2.3 Hz), 7.26 (d, 2H, J=3.0 Hz), 7.52-7.58 (m, 2H),7.72 (d, 1H, J=2.9 Hz). HPLC R_(t)=4.73 min (10-90% water:acetonitrilegradient, 100% pure).

EXAMPLE 61-(1-Benzyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(4-hydroxy-3-methoxy-benzyl)-thioureaCompound 3

[0573] Sodium hydride (60% in oil, 2.81 g, 10 mmol) was added to asolution of 4-hydroxy-3-methoxy-benzonitrile (10 g, 67 mmol) in DMF (100mL) at 0° C. Mixture was allowed to stir at ambient temperature for 30min. Bromomethylmethyl ether (6.4 mL, 70 mmol) was added to theresultant solution, and the solution was stirred at rt for 2 h. Thesolution was poured into ice water (˜400 mL). The product,3-Methoxy-4-methoxymethoxy-benzonitrile, was collected by filtration,washed generously with water, and allowed to air dry to give the productas a colorless solid 11.75 g (91%). The purity of the product wasestimated to be (95% by HPLC and H NMR, and the product was used withoutfurther purification in the subsequent step). ¹H NMR (CDCl₃): δ 3.51 (s,3H), 3.91 (s, 3H), 5.23 (s, 2H), 7.12 (d, J=1.8 Hz, 1H), 7.20 (d, J=8.4Hz, 1H) and 7.25 (d of d, J=8.4 & 1.8 Hz, 1H).

[0574] A solution of 3-methoxy-4-methoxymethoxy-benzonitrile (9.1 g,47.1 mmol) in THF (75 mL) was slowly added, via an addition funnel, to asolution of LAH in THF (1.0 M, 100 mL, 100 mmol) cooled on an ice bath.The resultant solution was heated to reflux for 4 h. The solution wascooled on an ice bath. Sequential addition of water (3.5 mL), 15%aqueous sodium hydroxide (7 mL) and water (10 mL) was carefully done viaan addition funnel. The inorganics were removed by filtration, andwashed generously with THF. The combined organic solutions were driedover sodium sulfate, and the solvent was evaporated under vacuum to givethe product, 5.3 g (57%). The product was used without purification inthe subsequent step. ¹H NMR (CDCl₃): δ 1.58 (br s, 1H), 3.51 (s, 3H),3.82 (s, 2H), 3.89 (s, 3H), 5.21 (s, 2H), 6.82 (d of d, J=8.4 & 1.8 Hz,1H), 6.90 (d, J=1.8 Hz) and 7.10 (d, J=8.1 Hz, 1H). MS: m/z 198 (M+H)⁺.

[0575] A solution of 3-methoxy-4-methoxymethoxybenzylamine (5.3 g, 26.9mmol) in ethyl acetate (50 mL) was added, via an addition funnel) to asolution of thiophosgene (2.15 mL, 28.2 mmol) and triethylamine (7.87mL, 56.5 mmol) in ethyl acetate (30 mL) at 0° C. The resultant solutionwas stirred at ambient temperature overnight. The solution was washedwith saturated aqueous sodium bicarbonate and dried over sodium sulfate.The solvent was evaporated in vacuo, and the residue was purified byflash chromatography on silica gel eluted with ethyl acetate/hexanes({fraction (1/9)} to {fraction (3/7)}) to give the product,4-isothiocyanatomethyl-2-methoxy-1-methoxymethoxy-benzene, as a waxy tansolid, 4.9 g (76%). ¹H NMR (CDCl₃): δ 3.51 (s, 3H), 3.91 (s, 3H), 4.64(s, 2 H), 5.23 (s, 2H), 6.83 (m, 2H) and 7.14 (d, J=8 Hz).

[0576] A solution ofcis-1-benzyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylaminehydrochloride (0.306 g, 1.01 mmol), diisopropylethylamine (0.264 mL,1.51 mmol) and 4-isothiocyanatomethyl-2-methoxy-1-methoxymethoxy-benzene(0.253 g, 1.06 mmol) in acetonitrile (10 mL) was stirred at ambienttemperature overnight. The solvent was evaporated in vacuo, and theresidue was purified by reverse phase preparative HPLC, on a C18 columneluted with a gradient of 40 to 90% acetonitrile in water with 0.1% TFA,to give the product,1-(1-benzyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(3-methoxy-4-methoxymethoxy-benzyl)-thiourea,0.21 g (41%). ¹H NMR (CDCl₃): δ 1.64 (br s, 1H), 1.85 (m, 1H), 2.04 (m,1H), 2.63 (m, 1H), 2.82 (m, 2H), 2.98 (m, 1H), 3.33 (m, 1H), 3.49 (s,3H), 3.78 (s, 3H), 3.84 (s, 3H), 4.32 (br s, 2H), 5.19 (s, 2H), 5.7(brs, 1H), 6.0 (brs, 1H), 6.64 (m, 3H), 6.80 (s, 1H), 6.91 (d, J=8.4 Hz,1H), 7.03 (d, J=8.2 Hz, 1H) and 7.11 to 7.28 (m, 5H). MS: m/z 507(M+H)⁺.

[0577] A solution of1-(1-benzyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(3-methoxy-4-methoxymethoxy-benzyl)-thiourea(0.21 g, 0.42 mmol) in isopropanol/acetonitrile (10 mL/10 mL) wastreated with concentrated hydrochloric acid (1 mL) and stirred atambient temperature for 30 min. The solvent was evaporated under astream of nitrogen, and the residue was partitioned betweendichloromethane and water. The organic layer was collected and thesolvent was evaporated. The product was purified by flashchromatography, on silica gel eluted with ethyl acetate/hexanes (½) togive the title product, compound 3, as a colorless solid, 0.184 g (95%).¹H NMR (CDCl₃): δ 1.83 (m, 1H), 2.05 (m, 1H), 2.67 (m, 1H), 2.81 (m,2H), 3.03 (br s, 1H), 3.78 (s, 3H), 3.84 (s, 3H), 4.25 (br s, 2H), 5.61(s, 2H), 6.59 to 6.68(m, 3H), 6.74 (s, 1H), 6.80 (d, J=8 Hz, 1H), 6.94(d, J=8.5 Hz, 1H) and 7.12 to 7.29 (m, 5H). MS: m/z 463 (M+H)⁺.

EXAMPLE 71-(1-Benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(2-oxy-isoquinolin-5-yl)-ureaCompound 85

[0578]

[0579] The aminotetralin urea 1 (0.150 g, 0.00035 mol) was dissolved in5 mL of dichloromethane. The solid m-chloroperbenzoic acid (0.066 g,0.00039 mol) was added and the reaction mixture was stirred at roomtemperature for 16 hours. Thin layer chromatography (silica gel,CH₂Cl₂/5% MeOH) indicated the presence of starting material. Anadditional portion of MCPBA was added (0.050 g) and stirring at roomtemperature was continued for another 4 hours. At the end of thisperiod, the reaction was complete was indicated by TLC. Saturated sodiumbicarbonate (25 mL) was cautiously added to the reaction mixture and theorganic layer was separated. The organic layer was washed with 25 mL ofbrine, dried over Na₂SO₄ and evaporated in vacuo. The residue waspurified by flash chromatography on silica gel eluting with CH₂Cl₂/4%MeOH. The product 2 was obtained as a light brown powder (0.120 g,0.00027 mol). ¹H NMR (CD₃OD): δ 1.8-2.1 (m, 2H), 2.9-3.1 (m, 4H), 3.6(m, 1H), 4.2 (m,1H), 6.6-6.9 (m, 3H), 7.1-7.3 (m, 5H), 7.6-7.8 (m, 2H),8.0 (bd, 1H), 8.2 (bt, 2H), 8.9 (s, 1H); MS (M+): 442.

EXAMPLE 81-(1-Benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(1-chloro-isoquinolin-5-yl)-ureaCompound 79

[0580] (1-Chloro-isoquinolin-5-yl)-carbamic acid phenyl ester (150 mgs,0.5 mmol), 1-Benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylaminehydrochloride (146 mgs, 0.5 mmol), and sodium bicarbonate (42 mgs, 0.5mmol) were combined and stirred for one hour in DMSO (4 ml) at ambienttemperature. The product was purified by directly injecting the crudereaction onto a reverse phase prep-HPLC (10-90% water:acetonitrilegradient). The appropriate fractions were lyophilized to yield1-(1-Benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(1-chloro-isoquinolin-5-yl)-urea(64 mgs, 28%) MS (MH⁺) 459; ¹H NMR (CD₃OD) δ 1.93-2.06 (m, 1H),2.09-2.13 (m, 1H), 2.91-3.07 (m, 4H), 3.40-3.42 (m, 1H), 4.07-4.10 (s,1H), 6.69-6.78 (m, 1H), 6.80-6.89 (m, 2H), 7.12-7.26 (m, 5H), 7.72 (t,1H, J=8.2 Hz), 7.83 (d, 1H, J=6.1 Hz), 8.19 (d, 1H, J=8.6 Hz), 8.17-8.24(m, 2H). HPLC R_(t)=4.04 min (50-90% water:acetonitrile gradient, 100%pure).

EXAMPLE 91-(1-Benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(1-methyl-isoquinolin-5-yl)-ureaCompound 80

[0581]

[0582] A. 1-Methyl-5-aminoisoquinoline (J.Med Chem., 1968, 11,700),(0.01 mole, 1.58 g) was dissolved in 20 mL of tetrahydrofuran (THF).Pyridine (0.011 mole, 0.88 g, 0.88 mL) was added followed by the carefuladdition of phenylchloroformate (0.011 mole, 1.72 g, 1.4 mL). Thereaction mixture immediately turned yellow and turbid. Stirring at roomtemperature was continued for 4 hours. The reaction mixture wasevaporated in vacuo. The residue was taken up in 50 mL ofdichloromethane, washed with 2×100 mL saturated sodium bicarbonate then2×100 mL of water. The organic layer was dried over sodium sulfate andevaporated in vacuo to give a thick dark yellow-brown oil. This oil wastriturated with diethylether to give the carbamate product 1 as ayellowish-brown solid.

[0583]¹H NMR (CDCl₃): δ 3.0 (bs, 3H), 7.2 (m, 3H), 7.3-7.4 (m, 2H),7.5-7.6 (m, 2H), 7.8 (bs, 1H), 8.2 (bs, 1H), 8.4 (bt, 1H). MS (MH+): 279

[0584] B. 1-Methyl-isoquinolin-5-yl-carbamic acid phenyl ester 1obtained in step A (0.001 mole, 0.278 g) was dissolved in 5 mL ofdimethylsulfoxide. Diisopropylethyl amine (0.0011 mole, 0.14 g, 0.2 mL)was added followed by the addition of1-benzyl-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydrochloride2 (0.0011 mole, 0.321 g). The reaction mixture was stirred at roomtemperature for 16 hours. The reaction mixture was then poured into 20mL of water containing 5 mL of 1N sodium hydroxide. The precipitatedsolid was collected by filtration. This solid was chromatographed onsilica gel eluting with a gradient of methylene chloride/3-10% methanol.Subsequently the product was further purified by recrystallization fromethyl acetate. The title compound 3 was obtained as an off-white solid(0.272 g, 0.0006 mole).

[0585]¹H NMR (CDCl₃): δ 1.8-1.9 (m, 2H), 2.7-2.8 (m, 4H), 2.95 (s, 3H),3.2-3.2 (m, 1H), 4.1-4.2 (m, 1H), 5.1 (d, 1H), 6.4-6.6 (m, 2H), 6.8 (d,1H), 6.9 (s, 1H), 7.0 (d, 1H), 7.1-7.2 (m, 2H), 7.4-7.5 (m, 2H), 7.7 (d,1H), 7.9 (d, 1H), 8.3 (d, 1H).

[0586] MS (MH+): 440

EXAMPLE 10Spiro{indan-2,1′-(1′,2′,3′,4′-tetrahydronaphthalene)-2′-yl}-3-isoquinolin-5-yl-ureaCompound 122

[0587]

[0588] A. 6-Fluoro-3,4-dihydro-1H-naphthalen-2-one (2.472 g, 15.06 mmol)was dissolved in 75 mL THF and cooled on an ice bath with stirring undernitrogen. o-Xylene dibromide (4.378 g, 16.59 mmol) was added to thecooled tetralone solution. Separately potassium tert-butoxide (3.73 g,33.2 mmol) was slurried in a combination of 75 mL THF and 10 mL tBuOH.The KOtBu slurry was added to the reaction mixture over a period of 15minutes. The reaction was stirred on the ice bath for one hour then atroom temperature for an additional hour after which time the entirereaction mixture was filtered over a pad of celite. The filtrate wasevaporated in vacuo to give a residue which was taken up in 100 mLdiethyl ether, washed twice with 50 mL 1N HCl and once with 50 mL brine.The organics were dried with MgSO₄, filtered and evaporated in vacuo togive the crude product which was purified by chromatography over silicagel eluting with 0-10% EtOAc in hexanes. Evaporation of the properfractions yielded the product as an off-white solid (3.09 g, 11.6 mmol).¹H NMR (CDCl₃): δ 7.33-7.17 (m, 4H), 7.07 (q, 1H), 6.93 (dd, 1H), 6.82(dt, 1H), 3.81 (d, 2H), 3.19 (m, 4H), 2.79 (t, 2H).

[0589] B. The spirotetralone from step A (3.06 g, 11.5 mmol) wasdissolved in 150 mL MeOH along with NH₄OAc (13.57 g, 176.1 mmol) andNaCNBH₃ (3.7 g, 59 mmol). The mixture was kept under a nitrogenatmosphere and heated to reflux for 3 hours. The reaction wasconcentrated in vacuo, mixed with 100 mL water and basified with 25 mL50% NaOH. The basified mixture was extracted three times with 50 mLmethylene chloride. The combined organics were washed once with 50 mlbrine, dried with Na₂SO₄, filtered and concentrated in vacuo to give thecrude free base. The free base was then dissolved in diethyl ether,acidified with ethereal HCl and evaporated in vacuo. The solid residuewas triturated with 50 mL hot EtOAc, filtered and dried to yield theproduct HCl salt as a white powder (2.867 g, 9.44 mmol). MS: M+H⁺=268.1;¹H NMR (d6-DMSO): δ 8.22 (br s, 3H), 7.33 (d, 1H), 7.24 (m, 3H), 7.01(d, 1H), 6.87 (d, 2H), 3.71 (m, 1H), 3.52 (d,1H), 3.38 (d, 1H), 3.11 (d,1H), 2.97 (m, 3H), 2.15 (m, 2H).

[0590] C. The spirotetralin salt from step B (0.304 g, 1.00 mmol) wasdissolved in 6 mL DMSO along with iPr₂NEt (0.38 mL, 2.2 mmol) and5-aminoisoquinoline phenylcarbamate (0.308 g, 1.02 mmol). The reactionwas stirred overnight then poured into 100 mL water. The solid whichformed was collected by filtration, rinsed with water then trituratedfirst with diethyl ether and finally with hexanes to give the producturea as a tan powder (0.287 g, 0.66 mmol). MS: M+H⁺=438.4; ¹H NMR(d6-DMSO): δ 9.27 (s, 1H), 8.67 (s, 1H), 8.52 (d, 1H), 8.38 (d, 1H),7.89 (d, 1H), 7.72 (d, 1H), 7.61 (t, 1H), 7.32 (d, 1H), 7.70 (m, 3H),7.04 (dd, 1H), 7.00-6.76 (m, 3H), 4.26 (m, 1H), 3.39 (m, 2H), 3.19 (d,1H), 3.05-2.88 (m, 3H), 2.18-1.92 (m, 2H).

EXAMPLE 11 Experimental Protocol for Resolution

[0591]

[0592] A. 6-F-α-(3-trifluoromethylbenzyl)-β-aminotetralin (1.931 g, 5.97mmol) was dissolved in 50 mL 1:1 iPrOH/MeOH. (R)-(−)-O-Methyl mandelicacid (0.992 g, 5.97 mmol) was added and the mixture was heated toreflux. An additional 170 mL 1:1 iPrOH/MeOH was added to bring the totalvolume of solvent to 220 mL and make a clear solution. The solution wasthen allowed to sit and cool overnight. The resulting crystallinematerial was collected by filtration, rinsed with a small amount of 1:1iPrOH/MeOH and dried. This batch of crystals was re-crystallized asbefore from 125 mL 1:1 iPrOH/MeOH. After filtration and drying, 625 mgof the salt of the aminotetralin with (R)-(−)-O-methyl mandelic acid(1.28 mmol) were obtained.

[0593] B. The combined mother liquors, filtrates, and rinsates fromabove were evaporated under vacuum. The residue was partitioned between200 mL Et₂O and 100 mL 10% Na₂CO₃ solution. The organics were separated,washed again with 100 mL 10% Na₂CO₃ and then with 100 mL brine. Theorganics were dried over Na₂SO₄, treated with charcoal, filtered andevaporated in vacuo to give the recovered aminotetralin (1.399 g, 4.33mmol). To this was added (S)-(+)-O-methyl mandelic acid (0.719 g, 4.33mmol) and 190 mL 1:1 iPrOH/MeOH and the mixture was heated to reflux togive a clear solution. The solution was then allowed to sit and coolovernight. The resulting crystalline material was collected byfiltration, rinsed with a small amount of 1:1 iPrOH/MeOH and dried. Thisbatch of crystals was re-crystallized as before from 140 mL 1:1iPrOH/MeOH. After filtration and drying, 759 mg of the salt of theaminotetralin with (S)-(+)-O-methyl mandelic acid (1.55 mmol) wereobtained.

[0594] C. Each of the mandelate salts thus prepared was separatelysuspended in 100 mL Et₂O, washed with 50 mL 10% Na₂CO₃ then with 50 mLbrine. The organics were then dried with Na₂SO₄, filtered and evaporatedin vacuo. The residue was dissolved in MeOH and excess ethereal HCl wasadded. The mixture was evaporated in vacuo and the resulting solids weretriturated with hexanes, filtered and dried under vacuum.

[0595] The HCl salt derived from the aminotetralin resolved with(R)-(−)-O-methyl mandelic acid (0.422 g, 1.17 mmol): [α]_(D)=−159.0°(c=1, MeOH).

[0596] The HCl salt derived from the aminotetralin resolved with(S)-(+)-O-methyl mandelic acid (0.506 g, 1.41 mmol): [α]_(D)=+159.1°(c=1, MeOH).

[0597] The ¹H NMR spectra of the hydrochloride salts were identical: ¹HNMR (d6-DMSO): 8.64 (br s, 3H), 7.59 (d, 1H), 7.52 (t, 1H), 7.42 (m,2H), 6.99 (dd, 1H), 6.63 (dt, 1H), 5.91 (dd, 1H), 3.59 (m, 1H),3.34-3.19 (m, 2H), 3.08 (m, 1H), 2.92 (m, 1H), 2.59 (d, 1H), 2.08 (m,2H). MS: M+H⁺=324.1

[0598] D. Other resolutions were performed in a similar manner to yieldthe results as shown in the table below. [α]_(D) of the HCl SaltsRacemic Amine Resolving Acid Solvent (c = 1, MeOH)

1:1 iPrOH:MeOH +159.1°/−159.0°

iPrOH +213.0°/−216.6°

14-67:1 EtOH:H₂O +70.7°/−71.4°

[0599] Using the procedures of the Examples above and the appropriatereagents, starting materials and purification methods known to thoseskilled in the art, other compounds of the present invention may beprepared including, but not limited to: TABLE 1 Mass Spectral Data forSelected Compounds Parent MW Peak No. Substituents on Formula (Ia)(calc) (obs) 3 R₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂—, R₃ is 462.6463.1 (3-OMe-4-OH)Ph, and X is S; (cis) 4 R₁ is H, R₂ is 3-Pyridinyl, mis 1, L is —CH₂—, R₃ is 477.6 477.8 (3-OMe-4-(Methoxymethyleneoxy)Ph,and X is S; (cis) 5 R₁ is H, R₂ is 3-Pyridinyl, m is 1, L is —CH₂—, R₃is (3-OMe-4-OH)Ph, and X is S; (cis) 6 R₁ is 6-OMe, R₂ is 3-Pyridinyl, mis 1, L is —CH₂—, 463.6 464.1 R₃ is (3-OMe-4-OH)Ph, and X is S; (cis) 7R₁ is 6-OMe, R₂ is —CH═CH₂, m is 1, L is —CH₂—, R₃ 456.6 457.1 is(3-OMe-4-(Methoxymethyleneoxy)Ph, and X is S; (cis) 8 R₁ is 6-OMe, R₂ is4-Imidazolyl, m is 1, L is —CH₂—, 452.6 453.1 R₃ is (3-OMe-4-OH)Ph, andX is S; 9 R₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂—, R₃ is 444.5 445.1(3,4-methylenedioxy)Ph, and X is O; 10 R₁ is 6-OMe, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is 460.6 461.1 (3,4-diOMe)Ph, and X is O; 11 R₁ is 6-OMe,R₂ is Ph, m is 1, L is —CH₂—, R₃ is 456.6 457.2 (4-tBu)Ph, and X is O;12 R₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂CH₂—, R₃ is 449.0 449.1(4-Cl)Ph, and X is O; 13 R₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂CH₂—,R₃ is 474.6 475.1 (3,4-diOMe)Ph, and X is O; 14 R₁ is 6-OMe, R₂ is Ph, mis 1, L is —CH₂—, R₃ is 460.6 461.1 (3,4-methylenedioxy)Ph, and X is S;15 R₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂—, R₃ is 476.6 477.1(3,4-diOMe)Ph, and X is S; 16 R₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂—,R₃ is 472.7 473.1 (4-tBu)Ph, and X is S; 17 R₁ is 6-OMe, R₂ is Ph, m is1, L is —CH₂CH₂—, R₃ is 465.1 465.0 (4-Cl)Ph, and X is S; 18 R₁ is6-OMe, R₂ is Ph, m is 1, L is —CH₂CH₂—, R₃ is 490.7 491.1 (3,4-diOMe)Ph,and X is S; 19 R₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂—, R₃ is 446.5447.1 (3-OMe-4-OH)Ph, and X is O; 21 R₁ is H, R₂ is Ph, m is 1, L is—CH₂—, R₃ is 476.6 476.7 (3-OMe-4-(Methoxymethyleneoxy)Ph, and X is S;(cis) 23 R₁ is H, R₂ is Ph, m is 1, L is —CH₂—, R₃ is 432.6 433.1(3-OMe-4-OH)Ph, and X is S; (cis) 24 R₁ is 6-OMe, R₂ is Ph, m is 1, L is—CH₂—, R₃ is 499.7 500.3 (4-N(Me)(C₅H₁₁))Ph, and X is O; 25 R₁ is 6-OMe,R₂ is Ph, m is 1, L is —CH₂—, R₃ is 511.7 512.3(4-[N(Me)(cyclohexyl)])Ph, and X is O; 26 R₁ is 6-F, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is 450.6 451.1 (3,4-diOMe)Ph, and X is S; (cis) 27 R₁ is6-OMe, R₂ is Ph, m is 1, L is —CH₂—, R₃ is 468.5 469.3 (4-CF₃)Ph, and Xis O; 28 R₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂—, R₃ is 469.4 469.1(3,4-diCl)Ph, and X is O; 29 R₁ is 6-OMe, R₂ is Ph, m is 1, L is—CH₂CH₂—, R₃ is 483.4 483.7 (3,4-diCl)Ph, and X is O; 30 R₁ is 6-OMe, R₂is Ph, m is 1, L is —CH₂—, R₃ is 484.6 485.6 (4-CF₃)Ph, and X is S; 31R₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂—, R₃ is 485.5 485.0(3,4-diCl)Ph, and X is S; 32 R₁ is 6-OMe, R₂ is Ph, m is 1, L is—CH₂CH₂—, R₃ is 499.5 499.0 (3,4-diCl)Ph, and X is S; 33 R₁ is 6-OMe, R₂is Ph, m is 1, L is a direct bond, 437.5 438.4 R₃ is 5-isoquinolinyl,and X is O; 34 R₁ is 6-OMe, R₂ is Ph, m is 1, L is a direct bond, 437.5438.7 R₃ is 3-quinolinyl, and X is O; 35 R₁ is 6-OMe, R₂ is Ph, m is 1,L is a direct bond, 452.5 453.1 R₃ is 8-(2-naphtholyl), and X is O; 36R₁ is H, R₂ is H, m is 0, L is a direct bond, R₃ is 317.4 359.15-isoquinolinyl, and X is O; (MeCN) 37 R₁ is 6-F, R₂ is H, m is 0, L isa direct bond, R₃ is 335.4 336.2 5-isoquinolinyl, and X is O; 38a R₁ is6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is 425.5 426.35-isoquinolinyl, and X is O; (racemate) 38b R₁ is 6-F, R₂ is Ph, m is 1,L is a direct bond, R₃ is 425.5 426 5-isoquinolinyl, and X is O;(enantiomer 1) 38c R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃is 425.5 426 5-isoquinolinyl, and X is O; (enantiomer 2) 39 R₁ is 6-Br,R₂ is Ph, m is 1, L is a direct bond, R₃ is 486.4 485.9 5-isoquinolinyl,and X is O; (cis) 40 R₁ is 6,7-diOMe, R₂ is Ph, m is 1, L is a direct467.6 468.2 bond, R₃ is 5-isoquinolinyl, and X is O; (cis) 41 R₁ is7-Cl, R₂ is Ph, m is 1, L is a direct bond, R₃ is 441.9 442.05-isoquinolinyl, and X is O; (cis) 42 R₁ is 5-Cl, R₂ is Ph, m is 1, L isa direct bond, R₃ is 441.9 441.9 5-isoquinolinyl, and X is O; (cis) 43R₁ is H, R₂ is Ph, m is 1, L is a direct bond, R₃ is 407.5 408.25-isoquinolinyl, and X is O; 44 R₁ is 6-OMe, R₂ is (3-Cl)Ph, m is 1, Lis a direct 472.0 472.3 bond, R₃ is 5-isoquinolinyl, and X is O; (cis)45 R₁ is 6-OMe, R₂ is 3-Pyridinyl, m is 1, L is a direct 438.5 439.0bond, R₃ is 5-isoquinolinyl, and X is O; (cis) 46 R₁ is 6-OMe, R₂ is(3-Cl)Ph, m is 1, L is a direct 472.0 471.9 bond, R₃ is 5-isoquinolinyl,and X is O; (trans) 47 R₁ is 6-OMe, R₂ is 3-Pyridinyl, m is 1, L is adirect 438.5 438.8 bond, R₃ is 5-isoquinolinyl, and X is O; (trans) 48R₁ is 6,7-diOMe, R₂ is Ph, m is 1, L is a direct 467.6 468.2 bond, R₃ is5-isoquinolinyl, and X is O; (trans) 49 R₁ is 6-OMe, R₂ is (2-Cl)Ph, mis 1, L is a direct 472.0 473.3 bond, R₃ is 5-isoquinolinyl, and X is O;(cis) 50 R₁ is 6-OMe, R₂ is (4-Cl)Ph, m is 1, L is a direct 472.0 472.3bond, R₃ is 5-isoquinolinyl, and X is O; (cis) 51 R₁ is 6-OMe, R₂ is H,m is 0, L is a direct bond, R₃ 347.4 348.6 is 5-isoquinolinyl, and X isO; 52 R₁ is 6-OMe, R₂ is (2-Cl)Ph, m is 1, L is a direct 472.0 472.2bond, R₃ is 5-isoquinolinyl, and X is O; (trans) 53 R₁ is 6-OMe, R₂ is(2-CF₃)Ph, m is 1, L is a direct 505.5 506.4 bond, R₃ is5-isoquinolinyl, and X is O; 54 R₁ is 6-OMe, R₂ is (3-CF₃)Ph, m is 1, Lis a direct 505.5 506.4 bond, R₃ is 5-isoquinolinyl, and X is O; 55 R₁is 6-OMe, R₂ is (4-CF₃)Ph, m is 1, L is a direct 505.5 506.3 bond, R₃ is5-isoquinolinyl, and X is O; 56 R₁ is 6-OH, R₂ is Ph, m is 1, L is adirect bond, R₃ 423.5 424.2 is 5-isoquinolinyl, and X is O; 57 R₁ is H,R₂ is —CH═CH₂, m is 1, L is a direct bond, 357.4 358.2 R₃ is5-isoquinolinyl, and X is O; 58 R₁ is 6-Br, R₂ is H, m is 0, L is adirect bond, R₃ is 396.3 397.9 5-isoquinolinyl, and X is O; 59 R₁ is6-Cl, R₂ is H, m is 0, L is a direct bond, R₃ is 351.8 351.95-isoquinolinyl, and X is O; 60 R₁ is 6-F, R₂ is Ph, m is 1, L is —CH₂—,R₃ is 439.5 440.2 5-isoquinolinyl, and X is O; 61 R₁ is 7-Cl, R₂ is H, mis 0, L is a direct bond, R₃ is 351.8 351.9 5-isoquinolinyl, and X is O;62 R₁ is 8-Cl, R₂ is Ph, m is 1, L is a direct bond, R₃ is 441.9 441.95-isoquinolinyl, and X is O; 63 R₁ is 6-OMe, R₂ is (4-CN)Ph, m is 1, Lis a direct 462.6 463.2 bond, R₃ is 5-isoquinolinyl, and X is O; 64 R₁is 6-OMe, R₂ is (4-Br)Ph, m is 1, L is a direct 516.4 517.9 bond, R₃ is5-isoquinolinyl, and X is O; 65 R₁ is 6-Cl, R₂ is CN, m is 1, L is adirect bond, R₃ 390.0 390.9 is 5-isoquinolinyl, and X is O; (cis) 66 R₁is 6,7-diF, R₂ is Ph, m is 1, L is a direct bond, 443.5 443.9 R₃ is5-isoquinolinyl, and X is O; 67 R₁ is 6-F, R₂ is Ph, m is 1, L is adirect bond, R₃ is 440.5 441.1 8-(2-naphtholyl), and X is O; 68 R₁ is6-OMe, R₂ is —CH═CH₂, m is 1, L is a direct 387.5 388.4 bond, R₃ is5-isoquinolinyl, and X is O; 69 R₁ is 6-F, R₂ is —CH═CH₂, m is 1, L is adirect 375.4 376.4 bond, R₃ is 5-isoquinolinyl, and X is O; 70 R₁ is6-OMe, R₂ is (4-OMe)Ph, m is 1, L is a direct 467.6 468.2 bond, R₃ is5-isoquinolinyl, and X is O; (trans) 71 R₁ is 6-F, R₂ is Cyclopropyl, mis 1, L is a direct 389.5 390.5 bond, R₃ is 5-isoquinolinyl, and X is O;72 R₁ is 6-OMe, R₂ is (4-OMe)Ph, m is 1, L is a direct 467.6 468.2 bond,R₃ is 5-isoquinolinyl, and X is O; (cis) 73 R₁ is 6-OMe, R₂ is(2-OMe)Ph, m is 1, L is a direct 467.6 468.2 bond, R₃ is5-isoquinolinyl, and X is O; 74 R₁ is 6-OMe, R₂ is (4-Benzyloxy)Ph, m is1, L is a 543.4 544.1 direct bond, R₃ is 5-isoquinolinyl, and X is O; 75R₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH2—, R₃ is 4-Pyridinyl, and X isO; 76 R₁ is 6-F, R₂ is 2-Thienyl, m is 1, L is a direct 431.5 432.0bond, R₃ is 5-isoquinolinyl, and X is O; 77 R₁ is 6-OMe, R₂ is(2,6-diF)Ph, m is 1, L is a direct 473.5 474.4 bond, R₃ is5-isoquinolinyl, and X is O; 81a R₁ is 6-F, R₂ is Ph, m is 1, L is adirect bond, R₃ is 439.5 440 3-Me-5-isoquinolinyl, and X is O; (cis)(enantiomer 1) 81b R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃is 439.5 440 3-Me-5-isoquinolinyl, and X is O; (cis) (enantiomer 2) 85aR₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is 441.5 4425-isoquinolinyl-N-oxide, and X is O; (cis) (enantiomer 1) 85b R₁ is 6-F,R₂ is Ph, m is 1, L is a direct bond, R₃ is 441.5 4425-isoquinolinyl-N-oxide, and X is O; (cis) (enantiomer 2) 86 R₁ is 6-Cl,R₂ is Ph, m is 1, L is a direct bond, R₃ 442 442 is 5-isoquinolinyl, andX is O; 87 R₁ is 6-OCH₃, R₂ is Ph, m is 1, L is a direct bond, 437.5438.2 R₃ is 5-isoquinolinyl, and X is O; (cis) (enantiomer 2) 88 R₁ is6-F, R₂ is 3-furanyl, m is 1, L is a direct bond, 415.5 416.4 R₃ is5-isoquinolinyl, and X is O; (cis) 89 R₁ is 6-OCH₃, R₂ is 3-thienyl, mis 1, L is a direct 443.6 444.4 bond, R₃ is 5-isoquinolinyl, and X is O90 R₁ is 6-OCH₃, R₂ is 2,4 di-F Ph, m is 1, L is a direct 473.5 474.4bond, R₃ is 5-isoquinolinyl, and X is O; (cis) 91 R₁ is 6-OCH₃, R₂ is2,4 di-F Ph, m is 1, L is a direct 473.5 474.5 bond, R₃ is5-isoquinolinyl, and X is O; (trans) 92 R₁ is 6-OCH₃, R₂ is Ph, m is 1,L is a direct bond, R₃ 437.5 438.1 is 5-isoquinolinyl, and X is O; (cis)(enantiomer 1) 93 R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is425.5 426.4 5-isoquinolinyl, and X is O; (cis) (enantiomer 1) 94 R₁ is6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is 425.5 426.65-isoquinolinyl, and X is O; (cis) (enantiomer 2) 95 R₁ is 6-Cl, R₂ isPh, m is 1, L is a direct bond, R₃ is 442.0 442.5 5-isoquinolinyl, and Xis O; (cis) 96 R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is441.5 442.7 5-isoquinolinyl-N-oxide, and X is O; (cis) (enantiomer 1) 97R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is 441.5 442.85-isoquinolinyl-N-oxide, and X is O; (cis) (enantiomer 2) 98 R₁ is 6-F,R₂ is Ph, m is 1, L is a direct bond, R₃ is 460.0 4604-Cl-5-isoquinolinyl, and X is O; (cis) 99 R₁ is 6-F, R₂ is Ph, m is 1,L is a direct bond, R₃ is 460.0 460 4-Cl-5-isoquinolinyl, and X is O;(cis) 100 R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is 439.5440.3 3-methyl-5-isoquinolinyl, and X is O; (cis) (enantiomer 1) 101 R₁is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is 439.5 440.33-methyl-5-isoquinolinyl, and X is O; (cis) (enantiomer 2) 102 R₁ is6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is 439.5 440.51-methyl-5-isoquinolinyl, and X is O; (cis) (enantiomer 1) 103 R₁ is6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is 439.5 440.51-methyl-5-isoquinolinyl, and X is O; (cis) (enantiomer 2) 104 R₁ is6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is 459.96 459.61-Cl-5-isoquinolinyl, and X is O; (cis) (enantiomer 1) 105 R₁ is 6-F, R₂is Ph, m is 1, L is a direct bond, R₃ is 460.0 459.91-Cl-5-isoquinolinyl, and X is O; (cis) (enantiomer 2) 106 R₁ is 6-Cl,R₂ is Ph, m is 1, L is a direct bond, R₃ is 457.9 459.05-isoquinolinyl-N-oxide, and X is O; (cis) 107 R₁ is 6-F, R₂ is 4-CF₃Ph, m is 1, L is a direct bond, 493.5 494.5 R₃ is 5-isoquinolinyl, and Xis O; (cis) 108 R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is494.4 494 1,3-diCl-5-isoquinolinyl, and X is O; (cis) 109 R₁ is 6-F, R₂is Ph, m is 1, L is a direct bond, R₃ is 494.4 4941,3-diCl-5-isoquinolinyl, and X is O; (cis) 110 R₁ is 6-F, R₂ is 3-CF₃Ph, m is 1, L is a direct bond, 493.5 494.6 R₃ is 5-isoquinolinyl, and Xis O; (±cis) 111 R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is460.0 460 8-Cl-5-isoquinolinyl, and X is O; (cis) 112 R₁ is 6-F, R₂ isPh, m is 1, L is a direct bond, R₃ is 508.6 5091-piperidinyl-5-isoquinolinyl, and X is O; (cis) 113 R₁ is 6-F, R₂ isPh, m is 1, L is a direct bond, R₃ is 455.5 456 1-OCH₃-5-isoquinolinyl,and X is O; (cis) 114 R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond,R₃ is 443.5 444 1-F-5-isoquinolinyl, and X is O; (cis) 115 R₁ is 6-F, R₂is Ph, m is 1, L is a direct bond, R₃ is 468.6 4691-N,N-dimethyl-5-isoquinolinyl, and X is O; (cis) 116 R₁ is 6-Cl, R₂ isnil, m is nil, R₃ is 1-CH₃- 365.9 366.0 5-isoquinolinyl, and X is O 117R₁ is 6-Cl, R₂ is nil, m is nil, R₃ is 1-Cl- 386.3 386.15-isoquinolinyl, and X is O 118 R₁ is 6-F, R₂ is 3-CF₃ Ph, m is 1, L isa direct bond, 493.5 494.6 R₃ is 5-isoquinolinyl, and X is O;(cis)(enantiomer 1) 119 R₁ is 6-F, R₂ is 3-CF₃ Ph, m is 1, L is a directbond, 493.5 494.6 R₃ is 5-isoquinolinyl, and X is O; (cis)(enantiomer 2)120 R₁ is 6-F, R₂ is 3-CF₃ Ph, m is 1, L is a direct bond, 509.5 510.2R₃ is 5-isoquinolinyl-N-oxide, and X is O; (cis) (enantiomer 1) 121 R₁is 6-F, R₂ is 3-CF₃ Ph, m is 1, L is a direct bond, 509.5 510.2 R₃ is5-isoquinolinyl-N-oxide, and X is O; (cis) (enantiomer 2) 122 R₁ is 6-F,R₂ is spiro-2-indanyl, L is a direct bond, 437.5 438.4 R₃ is5-isoquinolinyl, and X is O 123 R₁ is 6-F, R₂ is 4-Cl,3-CF₃ Ph, m is 1,L is a direct 527.9 528.3 bond, R₃ is 5-isoquinolinyl, and X is O; (cis)124 R₁ is 6-Cl, R₂ is Ph, m is 1, L is a direct bond, R₃ is 442.0 442.21-CH₃-5-isoquinolinyl, and X is O; (cis) (enantiomer 1) 125 R₁ is 6-Cl,R₂ is Ph, m is 1, L is a direct bond, R₃ is 442.0 442.21-CH₃-5-isoquinolinyl, and X is O; (cis) (enantiomer 2) 126 R₁ is 6-Cl,R₂ is Ph, m is 1, L is a direct bond, R₃ is 442.0 442.21-CH₃-5-isoquinolinyl, and X is O; (trans) (enantiomer 1) 127 R₁ is6-Cl, R₂ is Ph, m is 1, L is a direct bond, R₃ is 442.0 442.21-CH₃-5-isoquinolinyl, and X is O; (trans) (enantiomer 2)

Biological Examples EXAMPLE 1 Human or Rat VR₁ Binding Assay

[0600] Compounds of the present invention were tested for their abilityto inhibit the binding of [³H] RTX to hVR1 receptors in a [³H] RTXbinding assay as previously described (Zhang, Sui-Po. Improved ligandbinding assays for vanilloid receptors. PCT Int. Appl. (2002), 29 pp.CODEN: PIXXD2 WO 0233411 A1 20020425 AN 2002:315209; Grant, Elfrida R.;Dubin, Adrienne E.; Zhang, Sui-Po; Zivin, Robert A.; Zhong, ZhongSimultaneous intracellular calcium and sodium flux imaging in humanvanilloid receptor 1 (VR1)-transfected human embryonic kidney cells: amethod to resolve ionic dependence of VR1-mediated cell death. Journalof Pharmacology and Experimental Therapeutics (2002), 300(1), 9-17.)

[0601] HEK293 cells were transfected with human VR1 vanilloid receptorsand washed with Hank's Balanced Salt Solution, dissociated with celldissociation buffer (Sigma), and then centrifuged at 1000×g for 5 min.Cell pellets were homogenized in cold 20 mM HEPES buffer, pH 7.4,containing 5.8 mM NaCl, 320 mM sucrose, 2 mM MgCl₂, 0.75 CaCl₂ and 5 mMKCl and centrifuged at 1000×g for 15 min. The resultant supernate wasthen centrifuged at 40000×g for 15 min. The pelleted membranes were keptin an −80° C. freezer.

[0602] Approximately 120 μg protein/ml from membranes were incubatedwith indicated concentrations of [³H] RTX in 0.5 ml of the HEPES buffer(pH 7.4) containing 0.25 mg/mL fatty acid-free bovine serum albumin at37° C. for 60 min. The reaction mixture was then cooled to 4° C., 0.1mgα₁-acid glycoprotein added to each sample and incubated at 4° C. for15 min. The samples were centrifuged at 18500×g for 15 min. The tip ofthe microcentrifuge tube containing the pellet was cut off. Boundradioactivity was quantified by scintillation counting. Non-specificbinding was tested in the presence of 200 nM unlabeled RTX.

[0603] Alternatively, a binding assay using rat tissue was used. Ratspinal cord was homogenized twice with a Polytron and centrifuged at3000 rpm for 10 min in HEPES buffer containing 20 mM HEPES, pH 7.4, NaCl5.8 mM, sucrose 320 mM, MgCl₂ 2 mM, CaCl₂ 0.75 mM and KCl 5 mM. Thesupernatant was then centrifuged at 18,000 rpm for 20 min. The pelletwas saved in a tube and 10 ml assay buffer was added into the tube. Thepellet and buffer were mixed with a Polytron. The assay contained 120μg/ml membrane protein and 0.3-0.6 nM [³H]-RTX (NEN, Boston) in a totalvolume of 0.5 ml HEPES buffer. Following-incubation for 60 min at 37C,the samples were cooled down on ice, and 100 mg of a-acid glycoproteinwere added into the samples. After centrifugation at 13,000 rpm for 15min, the supernatant was aspirated and the tips of tubes were cut offand placed into 6 ml vials. Data were calculated according to theequation: % inhibition=(total binding−binding)*100/(total binding−nonspecific binding). Ki value values were calculated using a Prismprogram.

EXAMPLE 2 Human VR₁ Functional Assay

[0604] The functional activity of the test compounds was determined bymeasuring changes in intracellular calcium concentration using aCa⁺⁺-sensitive fluorescent dye and FLIPR™ technology. Increases in Ca⁺⁺concentration were readily detected upon challenge with capsaicin.

[0605] HEK293 Cells expressing human VR1 were grown on poly-D-lysinecoated 96 well black-walled plates (BD 354640) and 2 days later loadedwith Fluo-3/AM for 1 hour and subsequently tested for agonist-inducedincreases in intracellular Ca²⁺ levels using FLIPR™ technology. Cellswere challenged with test compounds (at varying concentrations) andintracellular Ca⁺⁺ was measured for 3 min prior to the addition ofcapsaicin to all wells to achieve a final concentration of 0.015 μMeliciting ˜80% maximal response. EC₅₀ or IC₅₀ values were determinedfrom dose-response studies. TABLE 2 Vanilloid In vitro assay dataCompound No. hVR1 K_(i) (nM) Rat VR1 Ki (nm) IC₅₀ or EC₅₀ (nM) 1 2530 NT780 2 31600 NT NT 3 98.9 NT 12 4 NT NT 460 5 NT NT 120 6 >10000 NT 260 7NT NT 2400 8 >10000 NT 10000 9 >10000 NT 3000 10 13000 NT 690 11 NT NT10000 12 NT NT >30000 13 3600 NT >30000 14 >10000 NT 10000 15 3110 NT440 16 NT NT >30000 17 NT NT >30000 18 NT NT >30000 19 258 NT 92 20 5520NT 10000 21 520 NT 520 23 98.2 NT 64 24 NT NT >30000 25 70900 NT 1000026 28.2 NT 69 27 NT NT >30000 28 NT NT >30000 29 NT NT >30000 30 NTNT >30000 31 NT NT >30000 32 NT NT >30000 33 3.37 NT 25 34 NT NT >3000035 9.64 NT 60 36 45.6 NT 41 37 24.9 NT 16 38a 1.76 NT 12 38b 0.72 NT NT38c 3.59 NT NT 39 0.89 NT 14 40 29.6 NT 195 41 4.58 NT 86 42 1.94 NT 1643 3.66 NT 20 44 1.96 NT 13 45 1540 NT 511 46 8.81 NT 540 47 1030 NT3000 48 19.3 NT 230 49 2.66 NT 130 50 1.8 NT 80 51 24 NT 72 52 12.3 NT250 53 0.48 NT 4.8 54 2.04 NT 5.1 55 1.55 NT 2.3 56 277 NT 200 57 15.4NT 120 58 2.62 NT 13 59 2.6 NT 9 60 4.99 NT 14 61 3.42 NT 5.7 62 7.59 NT22 63 16.5 NT 21 64 1.28 NT 22 65 NT NT 1000 66 1.82 NT 26 67 1.44 NT390 68 21.3 NT 97 69 2.19 NT 100 70 5.55 NT 460 71 0.84 NT 350 72 7.52NT 36 73 53.4 NT 110 74 11.3 NT 480 75 NT NT 730 76 3.81 NT 140 77 6.26NT 490 79a 10.8 NT NT 79b 32.3 NT NT 80a 5.32 NT NT 80b 25.1 NT NT 81a1.12 NT NT 81b 5.25 NT NT 82 103 NT NT 83 15.5 NT NT 84a 2700 NT NT 84b2730 NT NT 85a 45.4 NT NT 85b 50.2 NT NT 86 1.7 NT NT 87 NT 53.7 NT 8815.5 1270 NT 89 NT 1080 NT 90 NT 259 NT 91 NT 1480 NT 92 NT 7080 NT 933.59 517 NT 94 0.719 131 NT 95 1.7 217 NT 96 50.2 NT NT 97 45.4 NT NT 982730 100000 NT 99 2700 100000 NT 100 5.25 781 NT 101 1.12 53.1 NT 10225.1 100000 NT 103 5.32 101 NT 104 32.3 100000 NT 105 10.8 4922 NT 1068.6 2840 NT 107 0.93 28.7 NT 108 186 NT NT 109 29.2 100000 NT 110 0.531185 NT 111 NT 100000 NT 112 NT 100000 NT 113 NT 100000 NT 114 NT 100000NT 115 NT 100000 NT 116 NT 100000 NT 117 NT 100000 NT 118 2.16 169 NT119 0.5 152 NT 120 95.7 10000 NT 121 5.75 88.5 NT 122 73 1700 NT 123 NTNT NT 124 NT NT NT 125 NT NT NT 126 NT NT NT 127 NT NT NT

EXAMPLE 3 Broadly Stimulated Recombinant Human VR1 and Rat VR1Functional Assays

[0606] When nociceptors are exposed to tissue damaging stimuli, VR1receptors are activated by a plethora of stimuli. In an effort toidentify potent and efficacious antagonists at human and rat VR1 thatwere active under conditions simulating aspects of in vivo inflammationfunctional assays were developed using FLIPR to determine antagonistactivity against endogenous activators and stimuli likely to be presentin inflammation. Cell lines were constructed that stably expressedrecombinant rat VR1 (rVR1/HEK293). Cells were exposed to various stimuliat their EC₈₀, with the exception of the low pH and DTT stimuli.

[0607] Low pH (pH 5.9 (rat) or pH 6.5 (human). Cells were challenged for5 min with low pH solution which produced an increase in intracellularCa²⁺ which was subsequently reduced by exposure to antagonists. After 3min, other stimuli (a phorbol ester to induce phosphorylation,capsaicin, anandamide, redox agents) were applied to the cells todetermine the potency of antagonists to block those stimuli in an acidicenvironment. Cells were maintained in low pH in all steps subsequent tothe calcium dye loading step.

[0608] Phoshorylation by PKC. Previous studies have suggested thatphorbol esters activate VR1 via PKC phosphorylation [Premkumar, 2000#697; Vellani, 2001 #739]. These studies were corroborated and furtherstudies were performed to confirm that the phorbol ester effect was notdue to direct effects on the channel. The role of PKC was shownpharmacologically: phorbol-12-myristate-13-acetate (PMA) and otherphorbol esters active at PKC (but not the inactive 4α-phorbol) caused anincrease in intracellular Ca²⁺ that was mediated by VR1. The rank orderpotency for the panel of phorbol esters was similar to their rank orderpotency to block PKC. The PKC inhibitors bisindolylmaleimide (BIM) andstaurosporin blocked the PMA induced increase in Ca²⁺. The EC₅₀ for PMAat either rat or human recombinant VR1 was 90 nM. Cells were challengedwith 300 nM PMA (˜EC₈₀) after 3 min in the indicated antagonist. Theactive phorbol ester effect was blocked by RR and CPZ and requiredextracellular Ca²⁺. CPZ was more potent at the recombinant humancompared to the rat receptor.

[0609] Anandamide. Anandamide is a brain-derived cannabinoid ligand thatacts as a near full agonist at VR1 at low μM concentrations [Smart, 2000#507]. The EC₅₀ of anandamide at recombinant rat and human receptors was5 μM and 3 μM, respectively. The IC₅₀ was determined near the EC₈₀ ofanandamide (10 μM).

[0610] Reactive oxygen species: Disturbances in the regulatoryactivities of free radicals may play a role in inflammation [Winrow,1993]. Reactive oxygen species (ROS) such as H₂O₂ are formed in inflamedjoints. H₂O₂ directly activates VR1: the increase in intracellular Ca²⁺is in part blocked by VR1 antagonists and the response is dependent onextracellular Ca²⁺. The influx of Ca²⁺ through VR1 may contribute to theknown effects of ROS on signal transduction (e.g., phosphorylation ofproteins) and downstream regulation of gene transcription. The EC₈₀ forH₂O₂-induced Ca²⁺ flux in VR1/HEK cells was 0.015% H₂O₂ and thisconcentration was used to determine the IC₅₀ of VR1 antagonists.

[0611] Reducing agents: The reducing agent DTT also directly activatesVR1 [Vyklicky, 2002]. Cells were challenged with 5-10 mM DTT tostimulate VR1 after 3 min incubation in compound.

[0612] Compound 33 potently blocked the activation of human recombinantVR1 elicited by the agonists shown in Table 3. The increase inintracellular Ca²⁺ caused by acidic solutions, anandamide the PKCactivator PMA, and H₂O₂ was completely abolished by Compound 33 in adose dependent manner after 3 min incubation in antagonist (Table 3).The IC₅₀ values obtained in assays with low pH, anandamide and PMAstimuli were similar to the IC₅₀ values obtained againstcapsaicin-induced responses. Thus, Compound 33 is a potent antagonistagainst a panel of activators at the recombinant human receptor, with amore favorable pharmacological profile than the two most well studiedantagonists, capsazepine and ruthenium red. TABLE 3 Antagonism ofrecombinant human VR1 activated by a panel of stimuli in a Ca²⁺ influxin vitro assay (IC₅₀ in nM) H₂O₂ PKC PKC reactive Low phospho- phospho-oxygen pH Anandamide rylation rylation species Compound (nM) (nM) (nM)at low pH (nM) (nM) 33   23, 41  70 39  40 Capsazepine 110 160 370 (CPZ)Ruthenium 500 500 Red (RR)

[0613] The reference compounds used in these studies were the previouslycharacterized VR1 antagonists capsazepine (CPZ) and ruthenium red. CPZ,previously the most potent antagonist at human VR1, shows similarpotency (100-300 nM) at the human recombinant receptor to inhibit Ca²⁺activity induced by these stimuli (FIG. 1, left set of panels). For FIG.1, human (left) and rat (right) vanilloid 1 receptor expressed in HEK293 cells was stimulated by a number of different stimuli known toactivate VR1. FIG. 1 shows the IC₅₀ values of the competitive vanilloidantagonist capsazepine for inhibition of the calcium flux induced byeach of these activators. Note the similar potency of the compound atthe human receptor stimulated by various stimuli, but the lower potencyof the compound as an inhibitor of rat VR1.

[0614] In FIG. 2, the human (left) and rat (right) vanilloid 1 receptorexpressed in HEK 293 cells was stimulated by a number of differentstimuli known to activate VR1. The IC₅₀ values for inhibition by example#33 of the calcium flux induced by each of these activators is seen inFIG. 2.

[0615] CPZ has been shown to have significantly lower potency at the ratreceptor (recombinant and native receptors; [Mcintyre, 2001]). Sincemany of our animal models were in rat, we cloned the rat VR1 andexpressed it stably in HEK293 cells. We performed assays similar tothose described for the human recombinant receptor with the exceptionthat a lower pH was required in the Ca²⁺ influx assay at the ratrecombinant receptor.

[0616] As expected based on data from the literature, the CPZ profilerevealed low potency against heat-induced responses at the recombinantrat receptor [Nagy, 1999]. With the exception of the pore blocker RR,antagonists tended to have a lower potency at the rat compared to thehuman recombinant receptor. Importantly, Compound 33 potently andcompletely blocks rat recombinant VR1 activated by acidic solution,anandamide, and H₂O₂, and PMA at acidic pH (Table 4). TABLE 4 Antagonismof recombinant rat VR1 activated by a panel of stimuli in the Ca²⁺influx in vitro assay (IC₅₀ in nM) PKC PKC phospho- Low phospho-rylation pH Anandamide rylation at low Compound (nM) (nM) (nM) pH (nM)H₂O₂(NM) Cmpd 33 170 38 47 33 Capazepine 5000 1300 10000 10000 (CPZ)Ruthenium 1860 300 Red (RR)

[0617] Compound 33 potently blocked the activation of rat recombinantVR1 elicited by the agonists shown in Table 4. The increase inintracellular Ca²+ caused by acidic solutions, anandamide the PKCactivator PMA at low pH, and H₂O₂ was completely abolished by Compound33 in a dose dependent manner after 3 min incubation in antagonist(Table 4). The IC₅₀ values obtained in assays with low pH, anandamideand PMA stimuli were similar to the IC₅₀ values obtained againstcapsaicin-induced responses with the possible exception of the blockadeof the low pH response. Thus, Compound 33 is a potent antagonist againsta panel of activators at the recombinant rat receptor, with a morefavorable pharmacological profile than the two most well studiedantagonists, capsazepine and ruthenium red.

EXAMPLE 4 Electrophysiologic Functional Assay Using Dissociated Rat DRGCells

[0618] Compounds 42, 95, 101, 105 and 106 were tested for their activityon VR1 expressed endogenously on small rat dorsal root ganglion (DRG)neurons. DRG neurons from normal rats were dissociated (see methods inChaplan et al., 2003) and whole cell currents mediated by VR1 wererecorded using the whole cell patch clamp technique. The estimatedpotency of the compounds were determined either 1) by measuring theshift in the capsaicin-induced dose response in the presence of compoundor 2) by calculating the percent of capsaicin-induced current responsesin the presence of compound under conditions of limitedcapsaicin-induced desensitization (i.e., using 0 Ca²⁺-containing salinesolutions). Under these conditions, repeated application of capsaicinproduced similar current responses when 3 min recovery/washout periodswere allowed. Briefly in the first method, if a cell was responsive to300 nM capsaicin (˜EC₂₀), compound was applied to the cell at 100 or 300or 1000 nM to determine if the compound had intrinsic agonist activityand allow a 4-5 min incubation period prior to testing with capsaicin inthe presence of compound. After 4-5 min exposure to compound, 1 μMcapsaicin was applied in the presence of the same concentration ofcompound and incubated another 2-3 min. This was followed by applicationof 10 μM CAP in the presence of compound. Control cumulative capsaicindose response curves (filled squares) were obtained from a cell (theapproximate EC₅₀ in this cumulative dose response assay was ˜1 μM CAP;10 μM causes a maximal response). Vehicle caused no shift in thecapsaicin concentration dependence (not shown). The ability of 1 and 10μM CAP to cause an increased current after exposure to a compound of theinvention was compared to controls.

[0619] In the second method, a nociceptor was challenged with 0.3 uMcapsaicin while taking measurements of whole cell current using voltageramp protocols. After washout of the capsaicin, cells were exposed tothe compound for 4-5 min and subsequently challenged with 1 uM capsaicin(approximately the ED₈₀ at the native receptor in this experiments) inthe continued presence of compound. The current elicited near −100 mVwas measured during the first and second capsaicin exposure. The percentof the response elicited by 0.3 uM capsaicin obtained during theexposure to 1 uM capsaicin/compound was calculated. After washout, thecell was challenged with 10 uM capsaicin in the presence of compound andsubsequently washed again and challenged with capsaicin withoutcompound. TABLE 5 VR1 antagonists inhibit capsaicin-induced currents indissociated rat DRG neurons % of the initial CAP % of the initial CAPCompound response in response in concentration presence of 1 uM presenceof 10 uM Compound (uM) CAP CAP  42 0.3 0  95 0.03 78 1073 0.1 21 200 0.14 12 101 0.03 14 54 0.1 0 0 105 1 0 23 8 160 106 1 2 11 vehicle 330 115180 171 204

[0620] All compounds inhibited the response to 1 uM capsaicin. Theinhibition was done dependent (compounds 95 and 101). The response to 10uM capsaicin in the presence of compound was larger than the response to1 uM capsaicin/compound with the exception of the cell challenged with0.1 uM 101 which revealed no capsaicin induced current until thecompound was washed out and capsaicin alone was applied to the cell.These results indicate that Compounds 95 and 101 appeared to shift thecapsaicin dose response to the right in a dose dependent manner. PKB′values could not be determined because it is not known whether theblockade could not be surmounted by higher concentrations of capsaicin.Tested compounds had no detectable, reproducible effect on whole cellvoltage-activated currents in the DRG neurons studied.

EXAMPLE 5 Carrageenan Paw-Induced Thermal Hyperalgesia

[0621] Each rat was placed on a heated surface (51° C.) in order tomeasure the time necessary to elicit a response, and an initial(baseline) response time to a thermal stimuli was recorded for eachanimal. A response is defined as any shaking, licking, or tucking of thetreated paw or jumping. Animals not treated with a test compound respondin approximately 20 seconds. The maximal exposure time permitted is 60seconds to prevent tissue damage. Rats were injected with an irritant(e.g., 1% carrageenan solution in 0.9% saline) subcutaneously into thesub-plantar tissue of the left hind paw to stimulate an acuteinflammatory reaction.

[0622] Two hours later, the response time of the animal to the thermalstimulus was evaluated and compared to the animal's baseline responsetime. This shorter response time was recorded as percent hyperalgesia(%H). A cut-off value for %H (usually 75%) was used during analysis toensure that the animals were hyperalgesic. Animals were then dosed withtest drug or vehicle.

[0623] At some time(s) later (typically 45 and 90 minutes), the responsetime of the animal to the thermal stimulus was again evaluated. For eachtime point, a percent reversal of hyperalgesia (%R) was calculated usingthe following formula: %R=(Drug Latency−Carrageenan latency)/(Baselinelatency−Carrageenan latency). ED₅₀ values were calculated from %Robtained at several drug doses. CgHP ED₅₀ Cmpd No (mg/kg, po) 33 0.27657 0.354 4 0.804 17 19.958

[0624] Table 6. Percent Recovery at 1 mg/ml or ED₅₀ value (mg/kg, p.o.),each at 90 min. Compound % Recovery ED₅₀ (mg/kg, p.o.) 106 0.027 1050.394 107 0.92 110 64.3 120 83.0 121 80.1 124 55.2 125 63.9 126 46.0 12741.3

EXAMPLE 6 Evaluation of Action on Isolated Guinea Pig Bronchial Rings

[0625] Aminotetralin VR1 antagonists were tested for their potency toblock capsaicin-induced guinea pig bronchial ring contraction in astandard in vitro organ bath assay [Tucker, 2001]. Two mm rings ofbronchial tissue obtained from male guinea pigs (325 g) were suspendedin normal Krebs solution between two wire hooks under an initial loadingtension of 1 gram. The saline was maintained in a 5% CO₂ and 95% O₂atmosphere at 37° C. in the presence of indomethacin (5 μM). Asub-maximal dose of 5-Methylfurmethide (5Mef, 1 μM) was added to eachtissue to determine responsiveness using an isometric force transducer.After washout, tissues were exposed to compounds or vehicle for 30 min,treated with thiorphan (10 μM, 5% Na₂CO₃), and primed using KCl inincreasing linear concentrations from 1 mM at 1 mM intervals until aslight increase in muscle tone was induced (˜1% of 5Mef response). Aconcentration-response curve was then constructed using capsaicin (10nM-10 μM) increasing in 0.5 log unit increments. The dose response curvewas calculated as % max of the 5-Mef response and estimated pA₂ weredetermined [Tucker, 2001]).

[0626] Both Compound 38a (FIG. 3) and Compound 105 (FIG. 4) inhibitedcapsaicin-evoked bronchial ring contraction with an estimated pA₂ of 8.0and 6.2, respectively (Table 7). The potent antagonism ofcapsaicin-induced bronchial ring contraction indicated that thesecompounds may be effective inhibitors of cough and bronchial spasmmediated by VR1.

[0627] In FIG. 3, inhibition of capsaicin-induced contraction of guineapig bronchial rings is shown for an isolated tissue assay. The closedsymbols represent the capsaicin-only concentration-responserelationship, whereas the open symbols represent the capsaicin plusexample number 105 concentration-response. The inhibition appears as ashift to the right of the concentration-response curve, resulting in apA₂ (±SEM) value of 6.2±0.11.

[0628] In FIG. 4, inhibition of capsaicin-induced contraction of guineapig bronchial rings is shown for an isolated tissue assay. The closedsymbols represent the capsaicin-only concentration-responserelationship, whereas the open symbols represent the capsaicin plusexample number 38a concentration-response. The inhibition appears as ashift to the right of the concentration-response curve, resulting in apA₂ (±SEM) value of 8.0±0.02.

[0629] Table 7. VR1 Antagonist Blocked Capsaicin-Induced Guinea PigBronchial Ring Contraction in a Competitive Manner. Compound EstimatedpA₂  33 8.0 +/− 0.02 105 (1000 nM) 6.2 +/− 0.11

EXAMPLE 7 Antitussive Efficacy of VR1 Antagonists

[0630] The antitussive activity of intraperitoneally (IP) administeredcompound is assessed at a single dose level against capsaicin-inducedcough responses as compared to positive and vehicle controls. Thirty-sixmale Dunkin-Hartley guinea pigs (295-590 g, mean=425 g) are randomlyallocated to one of three groups (n=12 guinea pigs per group). Theblinding code is not revealed to the experimenter until coughs from allanimals are tallied. Guinea pigs are dosed IP at −60 min with vehicle(15% Solutol in 5% dextrose solution); the positive control codeine (25mg/kg), or test compound (20 mg/kg in 15% Solutol in 5% dextrosesolution). Individual guinea pigs are placed in an exposure chamber withan airflow of 3 L/min at −10 min to acclimatize. At ±0 min, coughresponses are induced by exposure to capsaicin aerosol (15 μM) generatedby an ultrasonic nebulizer at a nebulization rate of 0.6 ml/min for 4min. Coughs are counted throughout the 4 min capsaicin exposure and fora further 11 min. The mean±SEM number of capsaicin-induced coughresponses recorded in vehicle pre-treated guinea pigs was 3.0±0.5. Thislevel of response was reduced significantly to 0.58±0.15 coughs incodeine pre-treated guinea pigs (P<0.001) and is reduced in compoundpre-treated guinea pigs. ANOVA statistical analysis was used todetermine the level of significance.

[0631] The antitussive properties of test compounds are assessed in acitric acid-induced cough model as compared to positive and vehiclecontrols. Evaluation of a given compound in this paradigm is as follows:Six male Dunkin-Hartley guinea pigs (approximately 300-600 g) arerandomly assigned to each treatment group. Guinea pigs areintra-peritoneally (IP) injected with vehicle, test compound, orpositive control (codeine 25 mg/kg) 60 minutes prior to citric acidexposure. Individual guinea pigs are placed in an exposure chamber withan airflow of 3 L/min at −10 min to acclimatize. At ±0 min, coughresponses are induced by exposure to nebulized citric acid. Coughselicited during the 10-minute aerosol of citric acid and additional5-minute observation period are recorded and analysed for onset ofcough, and cough number and frequency. To eliminate bias, pre-treatmentsare randomised and the experiments are done blinded. The blinding codeis not revealed to the experimenter until coughs from all animals aretallied.

EXAMPLE 8 Rodent Colitis Model

[0632] 5% Dextran Sulfate Sodium administered in the drinking water ofmice or rats for 7 days results in an acute colitis with somemorphological changes that are similar to human ulcerative colitis.Among those changes are colon shortening, accumulation of neutrophilsand other inflammatory cells, decreases in colon weight, decreases inbody weight, tissue damage in the colon, and loss of stool consistency.

[0633] Each animal is dosed daily in the morning and late afternoon forBID dosing. Treatment with vehicle or test compound begins on day 0,immediately after initial body weights are taken, and ends on day 6.Water bottles are removed and replaced by graduated water bottlescontaining 5% DSS in indicated groups. Tap water remains on controlgroups only. Sufficient DSS drinking water is placed in graduated waterbottles and refilled each day to monitor daily output. Animals areweighed daily from day 0 to 7, and animal condition and the consistencyof stools recorded. Following sacrifice of the animal on day 7, thecolon is surgically removed from the distal rectum (anus) to thececal-colonic juncture and the colon length and weight measured. Colonslices may be obtained for histological evaluation. An active drugshould decrease or eliminate disruption of the epithelium and colonicfolds, dense inflammatory cell infiltrates, mucosal sloughing, etc. Inlife observations include monitoring for signs of gross toxicity and/orbehavioral changes, gross evaluation of the skin and fur, motor activityand any behavioral patterns with special attention to tremors,convulsions and diarrhea. Water consumption and body weights aremeasured daily. Scores include ratings for colon weight loss, stoolconsistency, colon damage, and colon shortening, and are used toassemble a Disease Activity Score. An increase in myeloperoxidaseactivity occurs in this model and is evaluated separately.

EXAMPLE 9 Uterine Pain Assessment

[0634] Female adult virgin Sprague Dawley rats (190-290 g) are used.Rats are anesthetized with pentobarbital (50 mg/kg IP). One uterine hornis approached via a small ventral midline laparotomy and tightly ligatedat its caudal end near the cervix with 3.0 silk suture to preventleakage of mustard oil through the cervix and vagina. Using a 22G needle0.1-0.2 ml of 10% mustard oil (Aldrich Chemical Co., Milwaukee Wis. USA;dissolved in mineral oil) or an equivalent volume of saline in shamcontrol rats, are injected into the uterine lumen. The abdominalincision is then closed and the rats allowed to recover from anesthesia.Rats are then transferred to individual Plexiglas cages in a quietenvironment (12/12 h light-dark cycle) with food and water ad libitumfor nonstop videotape recording for the duration of the experiment.Compounds or vehicle is administered by the intended route before(therapeutic) or after (prophylactic) acquisition of hyperalgesia. Therecording system consists of a camera connected to a videotape recorderwith a wide range of recording and reading speeds to allow for detailedanalysis of the movements of the rats. During the dark phase an infraredlight is used to permit continuous filming. Animal behavior is analyzedpost-hoc using a scoring system to count abnormal behaviors. Sixcharacteristic abnormal behaviors are expected in uterine inflammationrats: (1) hunching (2) hump-backed position (3) repeated licking of thelower abdomen/ipsilateral flank (4) repeated waves of contraction of theipsilateral oblique musculature with inward turning of the ipsilateralhind limb (5) stretching of the body (6) squashing of the lower abdomenagainst the cage floor. The effect of administered compounds on theintensity and frequency of pain related behaviors is quantitativelyassessed.

EXAMPLE 10 Models of Itch, Contact Dermatitis, Eczema and OtherManifestations of Dermal Allergy, Hypersensitivity and/or Inflammation

[0635] Vanilloid receptor modulators are tested in an animal model ofcontact dermatitis or itch, according to previously documented andvalidated methods, including but not limited to those described bySaint-Mezard et al. (2003), Gonzalez et al. (2001), Wille et al. (1998),Weisshaar et al. (1999) and Thomsen et al. (2002). In models of contactdermatitis, testing is conducted in mouse, guinea pig or human inresponse to a single (primary allergic dermatitis) or repeated(sensitized allergic dermatitis) topical or photomechanical exposure ofthe skin to one or more haptensselected from 12-myristate-13 acetate,picryl chloride, oxazolone, capsaicin, arachidonic acid, lactic acid,trans-retinoic acid or sodium lauryl sulfate. For increased sensitivity,animals are sensitized by pre-exposure to certain agents selected fromdinitrochlorobenzene, para-phenylenediamine or oxazolone. Forprophylactic or therapeutic testing, a vanilloid receptor modulator orvehicle control is administered to the test subjects by the enteral orparenteral route prior to or following hapten challenge. Significantdifferences in skin inflammation (erythema, edema, hyperthermia, etc.)for the test compound-treated subjects compared with vehicle-treatedsubjects demonstrate anti-allergy activity. The following additionaldependent measures are also collected and compared: skin and/or lymphnode levels of CF8+T cells, interleukin-1 alpha and beta, tumor necrosisfactor alpha, interferon gamma, nitric oxide, inducible nitric oxidesynthase and keratinocyte apoptosis, Fas expression and/or inflammatorymediator secretion.

[0636] In models of itch, testing is conducted in mouse, rat, guinea pigor human in response to the sub- or intra-dermal injection oriontophoresis of pruritogens select4ed from serotonin, compound 48/80,leukotriene B4, arachidonic acid, prostaglandin E2, histamine, substanceP, neurokinin A, neurokinin B, trypsin, hydroxyethylstarch orplatelet-activating factor singly or in combination with mosquito biteor injection of salivary gland extract therefrom. In some cases, animalsare inflamed by pre-exposure to certain agents, including but notlimited to sodium lauryl sulfate. For prophylactic or therapeutictesting, a vanilloid receptor modulator or vehicle control isadministered to the test subjects by the enteral or parenteral routeprior to or following pruritogen challenge. Cumulative scratchingbehavior and/or number of scratches per unit time are measured.Significant differences in scratching behavior for the testcompound-treated subjects compared with vehicle-treated subjectsdemonstrate anti-pruritic activity. The following additional dependentmeasures are collected and compared: skin inflammation (erythema, edema,hyperthermia, etc.), surface area of the wheal and flare, hyperalgesia,allodynia, plasma protein extravasation, inflammatory mediator releaseand serum immunoglobulin levels.

EXAMPLE 11 Models of Rhinitis and Other Manifestations of NasalHypersensitivity and/or Inflammation

[0637] Vanilloid receptor modulators are tested in an animal model ofrhinitis, according to previously documented and validated methods,including but not limited to those described by Hirayama et al. (2003),Tiniakov et al. (2003) and Magyar et al. (2002). Testing is conducted inmouse, guinea pig, dog or human in response to intranasal challenge withone or more irritants selected from bradykinin, histamine, pollens,dextran sulfate, 2,4-tolylene diisocyanate, Bordetella bronchiseptica,Pasteurella multodica or acetic acid. For increased sensitivity, animalsmay be sensitized by pre-exposure to ragweed or ovalbumin. Forprophylactic or therapeutic testing, a vanilloid receptor modulator orvehicle control is administered to the test subjects by the enteral orparenteral route prior to or following irritant challenge. The relevantdependent measures collected are plasma extravasation of the nasalmucosa, nasal eosinophilia or neutrophilia, nasal mucosal or nasalcavity lavage fluid levels of IL-5, interferon gamma, histamine or IgE,serum immunoglobulin levels, rhinorrhea, cumulative time spent sneezingor number of sneezes per unit time, nasal airway volume, peakinspiratory flow and resistance, intranasal pressure and nasal lesions.Significant differences in one or more of these measures for the testcompound-treated subjects compared with vehicle-treated subjectsdemonstrate anti-rhinitis activity.

EXAMPLE 12 Models of Anxiety, Panic Disorder and Other Non-AdaptiveStressful or Phobic Responses

[0638] Vanilloid receptor modulators are tested in an animal model ofanxiety, according to previously documented and validated methods,including but not limited to those reviewed by Imaizumi and Onodera(2000). Testing is conducted in mouse or rat and consists of methods tomeasure avoidance of aversive environmental stimuli selected from theGeller-type or Vogel-type anticonflict tests, the light/dark test, thehole-board test, the elevated plus-maze and the elevated T-maze. Priorto environmental exposure the test subject receives the prophylacticadministration one or more times of a vanilloid receptor modulator, orvehicle control, by the enteral or parenteral route. The cumulative timeor number of times spent engaged in the aversive behavior is measured.Significant differences in one or more of these measures for the testcompound-treated subjects compared with vehicle-treated subjects aretaken as evidence of anxiolytic activity.

1. A composition comprising a compound of Formula (I):

wherein: R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallyindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, fluorinated alkanyl andC₁₋₈alkanyloxy; C₁₋₈alkanyloxy optionally independently substituted withone or more substituents independently selected from the groupconsisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;fluorinated alkanyloxy; fluorinated alkanyl; C₁₋₈alkanylthio optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy; nitro; amino; C₁₋₈alkanylamino;C₁₋₈dialkanylamino; C₃₋₈cycloalkanylamino; cyano; carboxy;C₁₋₇alkanyloxycarbonyl; C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl;phenyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxyl,nitro, amino and cyano; aroyl; carbamoyl; amidino;(C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl; n is an integer from 1 to 3; m is an integerfrom 0 to 3; R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino; Lis a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl, orC₃₋₈cycloalkandiyl; R₃ is selected from the group consisting of phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₈alkanyl, halogen,C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; and heteroaryl optionally substituted withone to three substituents independently selected from the groupconsisting of C₁₋₈alkanyl, halogen, nitro, amino and cyano wherein saidheteroaryl is quinolinyl, quinolinyl-N-oxide, isoquinolinyl,isoquinolinyl-N-oxide, pyridyl, pyridyl-N-oxide pyrimidyl, furyl,thienyl or imidazolyl; R₄ is selected from the group consisting ofhydrogen and C₁₋₈alkanyl; R₅ is selected from the group consisting ofhydrogen and C₁₋₈alkanyl; X is selected from the group consisting of Oand S; and enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.
 2. A composition comprising acompound of Formula (I):

wherein: R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; fluoro; chloro; and C₁₋₈alkanyloxy; nis an integer from 1 to 3; m is an integer from 0 to 3; R₂ isindependently selected from the group consisting of hydrogen; hydroxy;C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl; fluoro;chloro; C₃₋₈cycloalkanyl; phenyl optionally substituted with one tothree substituents independently selected from the group consisting ofhalogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy,fluorinated alkanyl, cyano, nitro, amino, C₁₋₈alkanylamino, andC₁₋₈dialkanylamino; naphthyl optionally substituted with one to threesubstituents independently selected from the group consisting ofhalogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy,fluorinated alkanyl, cyano, nitro, amino, C₁₋₈alkanylamino, andC₁₋₈dialkanylamino; phenoxy optionally substituted with one to threesubstituents independently selected from the group consisting ofhalogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinated alkanyl,cyano and nitro; and heteroaryl optionally substituted with one to threesubstituents independently selected from the group consisting ofC₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl, pyrimidyl,furyl, thienyl or imidazolyl; pyrrolidino; and piperidino; L is a directbond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl, orC₃₋₈cycloalkandiyl; R₃ is selected from the group consisting of phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₈alkanyl, halogen,C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; and heteroaryl optionally substituted withone to three substituents independently selected from the groupconsisting of C₁₋₈alkanyl, halogen, nitro, amino and cyano wherein saidheteroaryl is quinolinyl, quinolinyl-N-oxide, isoquinolinyl,isoquinolinyl-N-oxide, pyridyl, pyridyl-N-oxide pyrimidyl, furyl,thienyl or imidazolyl; R₄ is selected from the group consisting ofhydrogen and C₁₋₈alkanyl; R₅ is selected from the group consisting ofhydrogen and C₁₋₈alkanyl; X is selected from the group consisting of Oand S; and enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.
 3. The composition of claim 2wherein R₂ is independently selected from the group consisting ofhydrogen; C₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl;C₃₋₈cyCloalkanyl; phenyl optionally substituted with one to threesubstituents independently selected from the group consisting of fluoro,chloro, bromo, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, and fluorinated alkanyl; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of fluoro, chloro, bromo, hydroxy, C₁₋₈alkanyl,C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, and fluorinated alkanyl; and aheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₆alkanyl andhalogen wherein said heteroaryl is pyridyl, pyrimidyl, furyl, thienyl orimidazolyl.
 4. The composition of claim 2 wherein L is a direct bond orC₁₋₈alkandiyl.
 5. The composition of claim 2 wherein R₃ is selected fromthe group consisting of naphthyl substituted with hydroxyl; quinolinyloptionally substituted with one or more substituents selected from thegroup consisting of methyl and chloro; quinolinyl-N-oxide; isoquinolinyloptionally substituted with one or more substituents selected from thegroup consisting of methyl and chloro and isoquinolinyl-N-oxide.
 6. Acomposition comprising a compound of Formula (I):

wherein: R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallyindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, fluorinated alkanyl andC₁₋₈alkanyloxy; C₁₋₈alkanyloxy optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen; fluorinated alkanyloxy; fluorinated alkanyl; C₁₋₈alkanylthiooptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, fluorinated alkanyl andC₁₋₈alkanyloxy; C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy; nitro; amino;C₁₋₈alkanylamino; C₁₋₈dialkanylamino; C₃₋₈cycloalkanylamino; cyano;carboxy; C₁₋₇alkanyloxycarbonyl; C₁₋₇alkanylcarbonyloxy; formyl;carbamoyl; phenyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxyl,nitro, amino and cyano; aroyl; carbamoyl; amidino;(C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl; n is an integer from 1 to 3; m is an integerfrom 0 to 3; R₂ is independently selected from the group consisting ofhydrogen; C₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl;C₃₋₈cycloalkanyl; phenyl optionally substituted with one to threesubstituents independently selected from the group consisting of fluoro,chloro, bromo, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of fluoro, chloro, bromo, hydroxy, C₁₋₈alkanyl,C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl; and aheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₆alkanyl andhalogen wherein said heteroaryl is pyridyl, pyrimidyl, furyl, thienyl orimidazolyl; L is a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl,C₂₋₈alkyndiyl, or C₃₋₈cycloalkandiyl; R₃ is selected from the groupconsisting of phenyl optionally substituted with one to threesubstituents independently selected from the group consisting ofC₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl,nitro, amino, di(C₁₋₁₈)alkanylamino, C₁₋₈alkanylamino and cyano;naphthyl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₈alkanyl,halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; and heteroaryloptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₈alkanyl, halogen, nitro, aminoand cyano wherein said heteroaryl is quinolinyl, quinolinyl-N-oxide,isoquinolinyl, isoquinolinyl-N-oxide, pyridyl, pyridyl-N-oxidepyrimidyl, furyl, thienyl or imidazolyl; R₄ is selected from the groupconsisting of hydrogen and C₁₋₈alkanyl; R₅ is selected from the groupconsisting of hydrogen and C₁₋₈alkanyl; X is selected from the groupconsisting of O and S; and enantiomers, diastereomers, tautomers,solvates, and pharmaceutically acceptable salts thereof.
 7. Thecomposition of claim 6 wherein R₁ is a substituent independentlyselected from the group consisting of hydrogen; hydroxy; fluoro; chloro;and C₁₋₈alkanyloxy.
 8. The composition of claim 6 wherein R₁ is asubstituent independently selected from the group consisting of fluoro;chloro; and C₁₋₈alkanyloxy.
 9. The composition of claim 6 wherein L is adirect bond or C₁₋₈alkandiyl.
 10. The composition of claim 6 wherein R₃is selected from the group consisting of naphthyl substituted withhydroxyl; quinolinyl optionally substituted with one or moresubstituents selected from the group consisting of methyl and chloro;quinolinyl-N-oxide; isoquinolinyl optionally substituted with one ormore substituents selected from the group consisting of methyl andchloro; and isoquinolinyl-N-oxide.
 11. A composition comprising acompound of Formula (I):

wherein: R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallyindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, fluorinated alkanyl andC₁₋₈alkanyloxy; C₁₋₈alkanyloxy optionally independently substituted withone or more substituents independently selected from the groupconsisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;fluorinated alkanyloxy; fluorinated alkanyl; C₁₋₈alkanylthio optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy; nitro; amino; C₁₋₈alkanylamino;C₁₋₈dialkanylamino; C₃₋₈cycloalkanylamino; cyano; carboxy;C₁₋₇alkanyloxycarbonyl; C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl;phenyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxyl,nitro, amino and cyano; aroyl; carbamoyl; amidino;(C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl; n is an integer from 1 to 3; m is an integerfrom 0 to 3; R₂ is independently selected from the group consisting ofhydrogen; C₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl;C₃₋₈cycloalkanyl; phenyl optionally substituted with one to threesubstituents independently selected from the group consisting of fluoro,chloro, bromo, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy and fluorinatedalkanyl; naphthyl optionally substituted with one to three substituentsindependently selected from the group consisting of fluoro, chloro,bromo, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy and fluorinated alkanyl;pyridyl; pyrimidyl; furyl; thienyl and imidazolyl; L is a direct bond,C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl, or C₃₋₈cycloalkandiyl; R₃is selected from the group consisting of phenyl optionally substitutedwith one to three substituents independently selected from the groupconsisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy, fluorinatedalkanyl, nitro, amino, di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano;naphthyl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₈alkanyl,halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; and heteroaryloptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₈alkanyl, halogen, nitro, aminoand cyano wherein said heteroaryl is quinolinyl, quinolinyl-N-oxide,isoquinolinyl, isoquinolinyl-N-oxide, pyridyl, pyridyl-N-oxide,pyrimidyl, furyl, thienyl or imidazolyl; R₄ is selected from the groupconsisting of hydrogen and C₁₋₈alkanyl; R₅ is selected from the groupconsisting of hydrogen and C₁₋₈alkanyl; X is selected from the groupconsisting of O and S; and enantiomers, diastereomers, tautomers,solvates, and pharmaceutically acceptable salts thereof.
 12. Thecomposition of claim 11 wherein R₁ is a substituent independentlyselected from the group consisting of hydrogen; hydroxy; fluoro; chloro;and C₁₋₈alkanyloxy.
 13. The composition of claim 11 wherein L is adirect bond or C₁₋₈alkandiyl.
 14. The composition of claim 11 wherein R₃is selected from the group consisting of naphthyl substituted withhydroxyl; quinolinyl optionally substituted with one or moresubstituents selected from the group consisting of methyl and chloro;quinolinyl-N-oxide; isoquinolinyl optionally substituted with one ormore substituents selected from the group consisting of methyl andchloro and isoquinolinyl-N-oxide.
 15. A composition comprising acompound of Formula (I):

wherein: R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallyindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, fluorinated alkanyl andC₁₋₈alkanyloxy; C₁₋₈alkanyloxy optionally independently substituted withone or more substituents independently selected from the groupconsisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;fluorinated alkanyloxy; fluorinated alkanyl; C₁₋₈alkanylthio optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy; nitro; amino; C₁₋₈alkanylamino;C₁₋₈dialkanylamino; C₃₋₈cycloalkanylamino; cyano; carboxy;C₁₋₇alkanyloxycarbonyl; C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl;phenyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxyl,nitro, amino and cyano; aroyl; carbamoyl; amidino;(C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl; n is an integer from 1 to 3; m is an integerfrom 0 to 3; R₂ is independently selected from the group consisting ofC₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl; C₃₋₈cycloalkanyl; phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of fluoro, chloro, bromo, andfluorinated alkanyl; L is a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl,C₂₋₈alkyndiyl, or C₃₋₈cycloalkandiyl; R₃ is selected from the groupconsisting of phenyl optionally substituted with one to threesubstituents independently selected from the group consisting ofC₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl,nitro, amino, di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; naphthyloptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₈alkanyl, halogen,C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; and heteroaryloptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₈alkanyl, halogen, nitro, aminoand cyano wherein said heteroaryl is quinolinyl, quinolinyl-N-oxide,isoquinolinyl, isoquinolinyl-N-oxide, pyridyl, pyridyl-N-oxide,pyrimidyl, furyl, thienyl or imidazolyl; R₄ is selected from the groupconsisting of hydrogen and C₁₋₈alkanyl; R₅ is selected from the groupconsisting of hydrogen and C₁₋₈alkanyl; X is selected from the groupconsisting of O and S; and enantiomers, diastereomers, tautomers,solvates, and pharmaceutically acceptable salts thereof.
 16. Thecomposition of claim 15 wherein R₁ is a substituent independentlyselected from the group consisting of hydrogen; hydroxy; fluoro; chloro;and C₁₋₈alkanyloxy.
 17. The composition of claim 15 wherein R₁ is asubstituent independently selected from the group consisting of fluoro;chloro; and C₁₋₈alkanyloxy.
 18. The composition of claim 15 wherein L isa direct bond or C₁₋₈alkandiyl.
 19. The composition of claim 15 whereinR₃ is selected from the group consisting of naphthyl substituted withhydroxyl; quinolinyl optionally substituted with one or moresubstituents selected from the group consisting of methyl and chloro;quinolinyl-N-oxide; isoquinolinyl optionally substituted with one ormore substituents selected from the group consisting of methyl andchloro and isoquinolinyl-N-oxide.
 20. A composition comprising acompound of Formula (I):

wherein: R₁ is a substituent independently selected from the groupconsisting of fluoro; chloro; C₁₋₈alkanyloxy; n is an integer from 1 to3; m is an integer from 0 to 3; R₂ is independently selected from thegroup consisting of hydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl;C₁₋₈alkylidenyl; C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl;phenyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, fluorinatedalkanyl, cyano, nitro, amino, C₁₋₈alkanylamino, and C₁₋₈dialkanylamino;naphthyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, fluorinatedalkanyl, cyano, nitro, amino, C₁₋₈alkanylamino, and C₁₋₈dialkanylamino;phenoxy optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinated alkanyl, cyano and nitro; andheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₆alkanyl andhalogen wherein said heteroaryl is pyridyl, pyrimidyl, furyl, thienyl orimidazolyl; pyrrolidino; and piperidino; L is a direct bond,C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl, or C₃₋₈cycloalkandiyl; R₃is selected from the group consisting of phenyl optionally substitutedwith one to three substituents independently selected from the groupconsisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy, fluorinatedalkanyl, nitro, amino, di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano;naphthyl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₈alkanyl,halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; and heteroaryloptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₈alkanyl, halogen, nitro, aminoand cyano wherein said heteroaryl is quinolinyl, quinolinyl-N-oxide,isoquinolinyl, isoquinolinyl-N-oxide, pyridyl, pyridyl-N-oxide,pyrimidyl, furyl, thienyl or imidazolyl; R₄ is selected from the groupconsisting of hydrogen and C₁₋₈alkanyl; R₅ is selected from the groupconsisting of hydrogen and C₁₋₈alkanyl; X is selected from the groupconsisting of O and S; and enantiomers, diastereomers, tautomers,solvates, and pharmaceutically acceptable salts thereof.
 21. Thecomposition of claim 20 wherein R₂ is independently selected from thegroup consisting of hydrogen; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; C₃₋₈cycloalkanyl; phenyl optionally substituted withone to three substituents independently selected from the groupconsisting of fluoro, chloro, bromo, hydroxy, C₁₋₈alkanyl,C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, and fluorinated alkanyl;naphthyl optionally substituted with one to three substituentsindependently selected from the group consisting of fluoro, chloro,bromo, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, andfluorinated alkanyl; and a heteroaryl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl, pyrimidyl,furyl, thienyl or imidazolyl.
 22. The composition of claim 20 wherein Lis a direct bond or C₁₋₈alkandiyl.
 23. The composition of claim 20wherein R₃ is selected from the group consisting of naphthyl substitutedwith hydroxyl; quinolinyl optionally substituted with one or moresubstituents selected from the group consisting of methyl and chloro;quinolinyl-N-oxide; isoquinolinyl optionally substituted with one ormore substituents selected from the group consisting of methyl andchloro and isoquinolinyl-N-oxide.
 24. A composition comprising acompound of Formula (I):

wherein: R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallyindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, fluorinated alkanyl andC₁₋₈alkanyloxy; C₁₋₈alkanyloxy optionally independently substituted withone or more substituents independently selected from the groupconsisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;fluorinated alkanyloxy; fluorinated alkanyl; C₁₋₈alkanylthio optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy; nitro; amino; C₁₋₈alkanylamino;C₁₋₈dialkanylamino; C₃₋₈cycloalkanylamino; cyano; carboxy;C₁₋₇alkanyloxycarbonyl; C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl;phenyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxyl,nitro, amino and cyano; aroyl; carbamoyl; amidino;(C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl; n is 1; m is an integer from 0 to 3; R₂ isindependently selected from the group consisting of hydrogen; hydroxy;C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl; fluoro;chloro; C₃₋₈cycloalkanyl; phenyl optionally substituted with one tothree substituents independently selected from the group consisting ofhalogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy,fluorinated alkanyl, cyano, nitro, amino, C₁₋₈alkanylamino, andC₁₋₈dialkanylamino; naphthyl optionally substituted with one to threesubstituents independently selected from the group consisting ofhalogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy,fluorinated alkanyl, cyano, nitro, amino, C₁₋₈alkanylamino, andC₁₋₈dialkanylamino; phenoxy optionally substituted with one to threesubstituents independently selected from the group consisting ofhalogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinated alkanyl,cyano and nitro; and heteroaryl optionally substituted with one to threesubstituents independently selected from the group consisting ofC₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl, pyrimidyl,furyl, thienyl or imidazolyl; pyrrolidino; and piperidino; L is a directbond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl, orC₃₋₈cycloalkandiyl; R₃ is selected from the group consisting of phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₈alkanyl, halogen,C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; and heteroaryl optionally substituted withone to three substituents independently selected from the groupconsisting of C₁₋₈alkanyl, halogen, nitro, amino and cyano wherein saidheteroaryl is quinolinyl, quinolinyl-N-oxide, isoquinolinyl,isoquinolinyl-N-oxide, pyridyl, pyridyl-N-oxide, pyrimidyl, furyl,thienyl or imidazolyl; R₄ is selected from the group consisting ofhydrogen and C₁₋₈alkanyl; R₅ is selected from the group consisting ofhydrogen and C₁₋₈alkanyl; X is selected from the group consisting of Oand S; and enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.
 25. The composition of claim24 wherein R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; fluoro; chloro; and C₁₋₈alkanyloxy. 26.The composition of claim 24 wherein R₁ is a substituent independentlyselected from the group consisting of fluoro; chloro; andC₁₋₈alkanyloxy.
 27. The composition of claim 24 wherein R₂ isindependently selected from the group consisting of hydrogen;C₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl; C₃₋₈cycloalkanyl; phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of fluoro, chloro, bromo, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, and fluorinatedalkanyl; naphthyl optionally substituted with one to three substituentsindependently selected from the group consisting of fluoro, chloro,bromo, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, andfluorinated alkanyl; and a heteroaryl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl, pyrimidyl,furyl, thienyl or imidazolyl.
 28. The composition of claim 24 wherein Lis a direct bond or C₁₋₈alkandiyl.
 29. The composition of claim 24wherein R₃ is selected from the group consisting of naphthyl substitutedwith hydroxyl; quinolinyl optionally substituted with one or moresubstituents selected from the group consisting of methyl and chloro;quinolinyl-N-oxide; isoquinolinyl optionally substituted with one ormore substituents selected from the group consisting of methyl andchloro and isoquinolinyl-N-oxide.
 30. A composition comprising acompound of Formula (I):

wherein: R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallyindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, fluorinated alkanyl andC₁₋₈alkanyloxy; C₁₋₈alkanyloxy optionally independently substituted withone or more substituents independently selected from the groupconsisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;fluorinated alkanyloxy; fluorinated alkanyl; C₁₋₈alkanylthio optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy; nitro; amino; C₁₋₈alkanylamino;C₁₋₈dialkanylamino; C₃₋₈cycloalkanylamino; cyano; carboxy;C₁₋₇alkanyloxycarbonyl; C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl;phenyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxyl,nitro, amino and cyano; aroyl; carbamoyl; amidino;(C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl; n is an integer from 1 to 3; m is an integerfrom 0 to 1; R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino; Lis a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl, orC₃₋₈cycloalkandiyl; R₃ is selected from the group consisting of phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₈alkanyl, halogen,C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; and heteroaryl optionally substituted withone to three substituents independently selected from the groupconsisting of C₁₋₈alkanyl, halogen, nitro, amino and cyano wherein saidheteroaryl is quinolinyl, quinolinyl-N-oxide, isoquinolinyl,isoquinolinyl-N-oxide, pyridyl, pyridyl-N-oxide, pyrimidyl, furyl,thienyl or imidazolyl; R₄ is selected from the group consisting ofhydrogen and C₁₋₈alkanyl; R₅ is selected from the group consisting ofhydrogen and C₁₋₈alkanyl; x is selected from the group consisting of Oand S; and enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.
 31. The composition of claim30 wherein R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; fluoro; chloro; and C₁₋₈alkanyloxy. 32.The composition of claim 30 wherein R₁ is a substituent independentlyselected from the group consisting of fluoro; chloro; andC₁₋₈alkanyloxy.
 33. The composition of claim 30 wherein R₂ isindependently selected from the group consisting of hydrogen;C₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl; C₃₋₈cycloalkanyl; phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of fluoro, chloro, bromo, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, and fluorinatedalkanyl; naphthyl optionally substituted with one to three substituentsindependently selected from the group consisting of fluoro, chloro,bromo, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, andfluorinated alkanyl; and a heteroaryl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl, pyrimidyl,furyl, thienyl or imidazolyl.
 34. The composition of claim 30 wherein Lis a direct bond or C₁₋₈alkandiyl.
 35. The composition of claim 30wherein R₃ is selected from the group consisting of naphthyl substitutedwith hydroxyl; quinolinyl optionally substituted with one or moresubstituents selected from the group consisting of methyl and chloro;quinolinyl-N-oxide; isoquinolinyl optionally substituted with one ormore substituents selected from the group consisting of methyl andchloro and isoquinolinyl-N-oxide.
 36. A composition comprising acompound of Formula (I):

wherein: R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallyindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, fluorinated alkanyl andC₁₋₈alkanyloxy; C₁₋₈alkanyloxy optionally independently substituted withone or more substituents independently selected from the groupconsisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;fluorinated alkanyloxy; fluorinated alkanyl; C₁₋₈alkanylthio optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy; nitro; amino; C₁₋₈alkanylamino;C₁₋₈dialkanylamino; C₃₋₈cycloalkanylamino; cyano; carboxy;C₁₋₇alkanyloxycarbonyl; C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl;phenyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxyl,nitro, amino and cyano; aroyl; carbamoyl; amidino;(C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl; n is an integer from 1 to 3; m is 1; R₂ isindependently selected from the group consisting of hydrogen; hydroxy;C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl; fluoro;chloro; C₃₋₈cycloalkanyl; phenyl optionally substituted with one tothree substituents independently selected from the group consisting ofhalogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy,fluorinated alkanyl, cyano, nitro, amino, C₁₋₈alkanylamino, andC₁₋₈dialkanylamino; naphthyl optionally substituted with one to threesubstituents independently selected from the group consisting ofhalogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy,fluorinated alkanyl, cyano, nitro, amino, C₁₋₈alkanylamino, andC₁₋₈dialkanylamino; phenoxy optionally substituted with one to threesubstituents independently selected from the group consisting ofhalogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinated alkanyl,cyano and nitro; and heteroaryl optionally substituted with one to threesubstituents independently selected from the group consisting ofC₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl, pyrimidyl,furyl, thienyl or imidazolyl; pyrrolidino; and piperidino; L is a directbond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl, orC₃₋₈cycloalkandiyl; R₃ is selected from the group consisting of phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₈alkanyl, halogen,C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; and heteroaryl optionally substituted withone to three substituents independently selected from the groupconsisting of C₁₋₈alkanyl, halogen, nitro, amino and cyano wherein saidheteroaryl is quinolinyl, quinolinyl-N-oxide, isoquinolinyl,isoquinolinyl-N-oxide, pyridyl, pyridyl-N-oxide, pyrimidyl, furyl,thienyl or imidazolyl; R₄ is selected from the group consisting ofhydrogen and C₁₋₈alkanyl; R₅ is selected from the group consisting ofhydrogen and C₁₋₈alkanyl; X is selected from the group consisting of Oand S; and enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.
 37. The composition of claim36 wherein R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; fluoro; chloro; and C₁₋₈alkanyloxy. 38.The composition of claim 36 wherein R₁ is a substituent independentlyselected from the group consisting of fluoro; chloro; andC₁₋₈alkanyloxy.
 39. The composition of claim 36 wherein R₂ isindependently selected from the group consisting of hydrogen;C₂₋₈alkenyl; C₃₋₈cycloalkanyl; phenyl optionally substituted with one tothree substituents independently selected from the group consisting offluoro, chloro, bromo, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, and fluorinated alkanyl; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of fluoro, chloro, bromo, hydroxy, C₁₋₈alkanyl,C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, and fluorinated alkanyl; and aheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₆alkanyl andhalogen wherein said heteroaryl is pyridyl, pyrimidyl, furyl, thienyl orimidazolyl.
 40. The composition of claim 36 wherein L is a direct bondor C₁₋₈alkandiyl.
 41. The composition of claim 36 wherein R₃ is selectedfrom the group consisting of naphthyl substituted with hydroxyl;quinolinyl optionally substituted with one or more substituents selectedfrom the group consisting of methyl and chloro; quinolinyl-N-oxide;isoquinolinyl optionally substituted with one or more substituentsselected from the group consisting of methyl and chloro andisoquinolinyl-N-oxide.
 42. A composition comprising a compound ofFormula (I):

wherein: R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallyindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, fluorinated alkanyl andC₁₋₈alkanyloxy; C₁₋₈alkanyloxy optionally independently substituted withone or more substituents independently selected from the groupconsisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;fluorinated alkanyloxy; fluorinated alkanyl; C₁₋₈alkanylthio optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy; nitro; amino; C₁₋₈alkanylamino;C₁₋₈dialkanylamino; C₃₋₈cycloalkanylamino; cyano; carboxy;C₁₋₇alkanyloxycarbonyl; C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl;phenyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxyl,nitro, amino and cyano; aroyl; carbamoyl; amidino;(C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl; n is an integer from 1 to 3; m is an integerfrom 0 to 3; R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino; Lis a direct bond or C₁₋₈alkandiyl; R₃ is selected from the groupconsisting of phenyl optionally substituted with one to threesubstituents independently selected from the group consisting ofC₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl,nitro, amino, di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; naphthyloptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₈alkanyl, halogen,C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; and heteroaryloptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₈alkanyl, halogen, nitro, aminoand cyano wherein said heteroaryl is quinolinyl, quinolinyl-N-oxide,isoquinolinyl, isoquinolinyl-N-oxide, pyridyl, pyridyl-N-oxide,pyrimidyl, furyl, thienyl or imidazolyl; R₄ is selected from the groupconsisting of hydrogen and C₁₋₈alkanyl; R₅ is selected from the groupconsisting of hydrogen and C₁₋₈alkanyl; X is selected from the groupconsisting of O and S; and enantiomers, diastereomers, tautomers,solvates, and pharmaceutically acceptable salts thereof.
 43. Thecomposition of claim 42 wherein R₁ is a substituent independentlyselected from the group consisting of hydrogen; hydroxy; fluoro; chloro;and C₁₋₈alkanyloxy.
 44. The composition of claim 42 wherein R₁ is asubstituent independently selected from the group consisting of fluoro;chloro; and C₁₋₈alkanyloxy.
 45. The composition of claim 42 wherein R₂is independently selected from the group consisting of hydrogen;C₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl; C₃₋₈cycloalkanyl; phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of fluoro, chloro, bromo, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, and fluorinatedalkanyl; naphthyl optionally substituted with one to three substituentsindependently selected from the group consisting of fluoro, chloro,bromo, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, andfluorinated alkanyl; and a heteroaryl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl, pyrimidyl,furyl, thienyl or imidazolyl.
 46. The composition of claim 42 wherein R₃is selected from the group consisting of naphthyl substituted withhydroxyl; quinolinyl optionally substituted with one or moresubstituents selected from the group consisting of methyl and chloro;quinolinyl-N-oxide; isoquinolinyl optionally substituted with one ormore substituents selected from the group consisting of methyl andchloro and isoquinolinyl-N-oxide.
 47. A composition comprising acompound of Formula (I):

wherein: R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallyindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, fluorinated alkanyl andC₁₋₈alkanyloxy; C₁₋₈alkanyloxy optionally independently substituted withone or more substituents independently selected from the groupconsisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;fluorinated alkanyloxy; fluorinated alkanyl; C₁₋₈alkanylthio optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy; nitro; amino; C₁₋₈alkanylamino;C₁₋₈dialkanylamino; C₃₋₈cycloalkanylamino; cyano; carboxy;C₁₋₇alkanyloxycarbonyl; C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl;phenyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxyl,nitro, amino and cyano; aroyl; carbamoyl; amidino;(C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl; n is an integer from 1 to 3; m is an integerfrom 0 to 3; R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino; Lis a direct bond; R₃ is selected from the group consisting of phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₈alkanyl, halogen,C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₁₈)alkanylamino,C₁₋₈alkanylamino and cyano; and heteroaryl optionally substituted withone to three substituents independently selected from the groupconsisting of C₁₋₈alkanyl, halogen, nitro, amino and cyano wherein saidheteroaryl is quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide,pyridyl, pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl; R₄ isselected from the group consisting of hydrogen and C₁₋₈alkanyl; R₅ isselected from the group consisting of hydrogen and C₁₋₈alkanyl; X isselected from the group consisting of O and S; and enantiomers,diastereomers, tautomers, solvates, and pharmaceutically acceptablesalts thereof.
 48. The composition of claim 47 wherein R₁ is asubstituent independently selected from the group consisting ofhydrogen; hydroxy; fluoro; chloro; and C₁₋₈alkanyloxy.
 49. Thecomposition of claim 47 wherein R₁ is a substituent independentlyselected from the group consisting of fluoro; chloro; andC₁₋₈alkanyloxy.
 50. The composition of claim 47 wherein R₂ isindependently selected from the group consisting of hydrogen;C₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl; C₃₋₈cycloalkanyl; phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of fluoro, chloro, bromo, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, and fluorinatedalkanyl; naphthyl optionally substituted with one to three substituentsindependently selected from the group consisting of fluoro, chloro,bromo, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, andfluorinated alkanyl; and a heteroaryl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl, pyrimidyl,furyl, thienyl or imidazolyl.
 51. The composition of claim 47 wherein R₃is selected from the group consisting of naphthyl substituted withhydroxyl; quinolinyl optionally substituted with one or moresubstituents selected from the group consisting of methyl and chloro;quinolinyl-N-oxide; isoquinolinyl optionally substituted with one ormore substituents selected from the group consisting of methyl andchloro and isoquinolinyl-N-oxide.
 52. A composition comprising acompound of Formula (I):

wherein: R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallyindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, fluorinated alkanyl andC₁₋₈alkanyloxy; C₁₋₈alkanyloxy optionally independently substituted withone or more substituents independently selected from the groupconsisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;fluorinated alkanyloxy; fluorinated alkanyl; C₁₋₈alkanylthio optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy; nitro; amino; C₁₋₈alkanylamino;C₁₋₈dialkanylamino; C₃₋₈cycloalkanylamino; cyano; carboxy;C₁₋₇alkanyloxycarbonyl; C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl;phenyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxyl,nitro, amino and cyano; aroyl; carbamoyl; amidino;(C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl; n is an integer from 1 to 3; m is an integerfrom 0 to 3; R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino; Lis a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl, orC₃₋₈cycloalkandiyl; R₃ is selected from the group consisting of phenylsubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, fluoro, chloro, bromo,C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; naphthyl substitutedwith one to three substituents independently selected from the groupconsisting of C₁₋₈alkanyl, fluoro, chloro, bromo, C₁₋₈alkanyloxy,hydroxy, fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; and heteroaryl optionally substituted withone to three substituents independently selected from the groupconsisting of C₁₋₈alkanyl, fluoro and chloro, wherein said heteroaryl isquinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl,pyridyl-N-oxide, pyrimidyl, furyl, thienyl or imidazolyl; R₄ is selectedfrom the group consisting of hydrogen and C₁₋₈alkanyl; R₅ is selectedfrom the group consisting of hydrogen and C₁₋₈alkanyl; X is selectedfrom the group consisting of O and S; and enantiomers, diastereomers,tautomers, solvates, and pharmaceutically acceptable salts thereof. 53.The composition of claim 52 wherein R₁ is a substituent independentlyselected from the group consisting of hydrogen; hydroxy; fluoro; chloro;and C₁₋₈alkanyloxy.
 54. The composition of claim 52 wherein R₁ is asubstituent independently selected from the group consisting of fluoro;chloro; and C₁₋₈alkanyloxy.
 55. The composition of claim 52 wherein R₂is independently selected from the group consisting of hydrogen;C₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl; C₃₋₈cycloalkanyl; phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of fluoro, chloro, bromo, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, and fluorinatedalkanyl; naphthyl optionally substituted with one to three substituentsindependently selected from the group consisting of fluoro, chloro,bromo, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, andfluorinated alkanyl; and a heteroaryl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl, pyrimidyl,furyl, thienyl or imidazolyl.
 56. The composition of claim 52 wherein Lis a direct bond or C₁₋₈alkandiyl.
 57. A composition comprising acompound of Formula (I):

wherein: R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallyindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, fluorinated alkanyl andC₁₋₈alkanyloxy; C₁₋₈alkanyloxy optionally independently substituted withone or more substituents independently selected from the groupconsisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;fluorinated alkanyloxy; fluorinated alkanyl; C₁₋₈alkanylthio optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy; nitro; amino; C₁₋₈alkanylamino;C₁₋₈dialkanylamino; C₃₋₈cycloalkanylamino; cyano; carboxy;C₁₋₇alkanyloxycarbonyl; C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl;phenyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxyl,nitro, amino and cyano; aroyl; carbamoyl; amidino;(C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl; n is an integer from 1 to 3; m is an integerfrom 0 to 3; R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino; Lis a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl, orC₃₋₈cycloalkandiyl; R₃ is selected from the group consisting of phenylsubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyloxy and hydroxy; naphthyl substitutedwith one to three substituents independently selected from the groupconsisting of C₁₋₈alkanyloxy and hydroxy; and heteroaryl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl and chloro wherein said heteroarylis quinolinyl-N-oxide, isoquinolinyl, isoquinolinyl-N-oxide, pyridyl andpyridyl-N-oxide; R₄ is selected from the group consisting of hydrogenand C₁₋₈alkanyl; R₅ is selected from the group consisting of hydrogenand C₁₋₈alkanyl; X is selected from the group consisting of O and S; andenantiomers, diastereomers, tautomers, solvates, and pharmaceuticallyacceptable salts thereof.
 58. The composition of claim 57 wherein R₁ isa substituent independently selected from the group consisting ofhydrogen; hydroxy; fluoro; chloro; and C₁₋₈alkanyloxy.
 59. Thecomposition of claim 57 wherein R₁ is a substituent independentlyselected from the group consisting of fluoro; chloro; andC₁₋₈alkanyloxy.
 60. The composition of claim 57-wherein R₂ isindependently selected from the group consisting of hydrogen;C₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl C₃₋₈cycloalkanyl; phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of fluoro, chloro, bromo, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, and fluorinatedalkanyl; naphthyl optionally substituted with one to three substituentsindependently selected from the group consisting of fluoro, chloro,bromo, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, andfluorinated alkanyl; and a heteroaryl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl, pyrimidyl,furyl, thienyl or imidazolyl.
 61. The composition of claim 57 wherein Lis a direct bond or C₁₋₈alkandiyl.
 62. A composition comprising acompound of Formula (I):

wherein: R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallyindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, fluorinated alkanyl andC₁₋₈alkanyloxy; C₁₋₈alkanyloxy optionally independently substituted withone or more substituents independently selected from the groupconsisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;fluorinated alkanyloxy; fluorinated alkanyl; C₁₋₈alkanylthio optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy; nitro; amino; C₁₋₈alkanylamino;C₁₋₈dialkanylamino; C₃₋₈cycloalkanylamino; cyano; carboxy;C₁₋₇alkanyloxycarbonyl; C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl;phenyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxyl,nitro, amino and cyano; aroyl; carbamoyl; amidino;(C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl; n is an integer from 1 to 3; m is an integerfrom 0 to 3; R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino; Lis a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl, orC₃₋₈cycloalkandiyl; R₃ is selected from the group consisting of naphthylsubstituted with hydroxyll; quinolinyl optionally substituted with oneor more substituents selected from the group consisting of methyl andchloro, quinolinyl-N-oxide, isoquinolinyl optionally substituted withone or more substituents selected from the group consisting of methyland chloro and isoquinolinyl-N-oxide; R₄ is selected from the groupconsisting of hydrogen and C₁₋₈alkanyl; R₅ is selected from the groupconsisting of hydrogen and C₁₋₈alkanyl; X is selected from the groupconsisting of O and S; and enantiomers, diastereomers, tautomers,solvates, and pharmaceutically acceptable salts thereof.
 63. Thecomposition of claim 62 wherein R₁ is a substituent independentlyselected from the group consisting of hydrogen; hydroxy; fluoro; chloro;and C₁₋₈alkanyloxy.
 64. The composition of claim 62 wherein R₁ is asubstituent independently selected from the group consisting of fluoro;chloro; and C₁₋₈alkanyloxy.
 65. The composition of claim 62 wherein R₂is independently selected from the group consisting of hydrogen;C₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl; C₃₋₈cycloalkanyl; phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of fluoro, chloro, bromo, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, and fluorinatedalkanyl; naphthyl optionally substituted with one to three substituentsindependently selected from the group consisting of fluoro, chloro,bromo, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, andfluorinated alkanyl; and a heteroaryl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl, pyrimidyl,furyl, thienyl or imidazolyl.
 66. The composition of claim 62 wherein Lis a direct bond or C₁₋₈alkandiyl.
 67. A composition comprising acompound of Formula (I):

wherein: R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallyindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, fluorinated alkanyl andC₁₋₈alkanyloxy; C₁₋₈alkanyloxy optionally independently substituted withone or more substituents independently selected from the groupconsisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;fluorinated alkanyloxy; fluorinated alkanyl; C₁₋₈alkanylthio optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy; nitro; amino; C₁₋₈alkanylamino;C₁₋₈dialkanylamino; C₃₋₈cycloalkanylamino; cyano; carboxy;C₁₋₇alkanyloxycarbonyl; C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl;phenyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxyl,nitro, amino and cyano; aroyl; carbamoyl; amidino;(C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl; n is an integer from 1 to 3; m is anintegerfrom 0 to 3; R₂ is independently selected from the groupconsisting of hydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl;C₁₋₈alkylidenyl; C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl;phenyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, fluorinatedalkanyl, cyano, nitro, amino, C₁₋₈alkanylamino, and C₁₋₈dialkanylamino;naphthyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, fluorinatedalkanyl, cyano, nitro, amino, C₁₋₈alkanylamino, and C₁₋₈dialkanylamino;phenoxy optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinated alkanyl, cyano and nitro; andheteroaryl optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₆alkanyl andhalogen wherein said heteroaryl is pyridyl, pyrimidyl, furyl, thienyl orimidazolyl; pyrrolidino; and piperidino; L is a direct bond,C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl, or C₃₋₈cycloalkandiyl; R₃is 2-hydroxynaphth-8-yl, isoquinolin-5-yl andisoquinolinyl-5-yl-N-oxide; R₄ is selected from the group consisting ofhydrogen and C₁₋₈alkanyl; R₅ is selected from the group consisting ofhydrogen and C₁₋₈alkanyl; X is selected from the group consisting of Oand S; and enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.
 68. The composition of claim67 wherein R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; fluoro; chloro; and C₁₋₈alkanyloxy. 69.The composition of claim 67 wherein R₁ is a substituent independentlyselected from the group consisting of fluoro; chloro; andC₁₋₈alkanyloxy.
 70. The composition of claim 67 wherein R₂ isindependently selected from the group consisting of hydrogen;C₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl; C₃₋₈cycloalkanyl; phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of fluoro, chloro, bromo, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, and fluorinatedalkanyl; naphthyl optionally substituted with one to three substituentsindependently selected from the group consisting of fluoro, chloro,bromo, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, andfluorinated alkanyl; and a heteroaryl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl, pyrimidyl,furyl, thienyl or imidazolyl.
 71. The composition of claim 67 wherein Lis a direct bond or C₁₋₈alkandiyl.
 72. A composition comprising acompound of Formula (I):

wherein: R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallyindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, fluorinated alkanyl andC₁₋₈alkanyloxy; C₁₋₈alkanyloxy optionally independently substituted withone or more substituents independently selected from the groupconsisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;fluorinated alkanyloxy; fluorinated alkanyl; C₁₋₈alkanylthio optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy; nitro; amino; C₁₋₈alkanylamino;C₁₋₈dialkanylamino; C₃₋₈cycloalkanylamino; cyano; carboxy;C₁₋₇alkanyloxycarbonyl; C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl;phenyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxyl,nitro, amino and cyano; aroyl; carbamoyl; amidino;(C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl; n is an integer from 1 to 3; m is an integerfrom 0 to 3; R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino; Lis a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl, orC₃₋₈cycloalkandiyl; R₃ is selected from the group consisting of phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₈alkanyl, halogen,C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; and heteroaryl optionally substituted withone to three substituents independently selected from the groupconsisting of C₁₋₈alkanyl, halogen, nitro, amino and cyano wherein saidheteroaryl is quinolinyl, quinolinyl-N-oxide, isoquinolinyl,isoquinolinyl-N-oxide, pyridyl, pyridyl-N-oxide, pyrimidyl, furyl,thienyl or imidazolyl; R₄ is hydrogen; R₅ is selected from the groupconsisting of hydrogen and C₁₋₈alkanyl; X is selected from the groupconsisting of O and S; and enantiomers, diastereomers, tautomers,solvates, and pharmaceutically acceptable salts thereof.
 73. Thecomposition of claim 72 wherein R₁ is a substituent independentlyselected from the group consisting of hydrogen; hydroxy; fluoro; chloro;and C₁₋₈alkanyloxy.
 74. The composition of claim 72 wherein R₁ is asubstituent independently selected from the group consisting of fluoro;chloro; and C₁₋₈alkanyloxy.
 75. The composition of claim 72 wherein R₂is independently selected from the group consisting of hydrogen;C₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl; C₃₋₈cycloalkanyl; phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of fluoro, chloro, bromo, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, and fluorinatedalkanyl; naphthyl optionally substituted with one to three substituentsindependently selected from the group consisting of fluoro, chloro,bromo, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, andfluorinated alkanyl; and a heteroaryl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl, pyrimidyl,furyl, thienyl or imidazolyl.
 76. The composition of claim 72 wherein Lis a direct bond or C₁₋₈alkandiyl.
 77. The composition of claim 72wherein R₃ is selected from the group consisting of naphthyl substitutedwith hydroxyl; quinolinyl optionally substituted with one or moresubstituents selected from the group consisting of methyl and chloro;quinolinyl-N-oxide; isoquinolinyl optionally substituted with one ormore substituents selected from the group consisting of methyl andchloro and isoquinolinyl-N-oxide.
 78. A composition comprising acompound of Formula (I):

wherein: R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallyindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, fluorinated alkanyl andC₁₋₈alkanyloxy; C ₁₋₈alkanyloxy optionally independently substitutedwith one or more substituents independently selected from the groupconsisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy one ormore substituents independently selected from the group consisting ofhalogen, fluorinated alkanyl and C₁₋₈alkanyloxy; fluorinated alkanyloxy;fluorinated alkanyl; C₁₋₈alkanylthio optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, fluorinated alkanyl and C₁₋₈alkanyloxy; C₃₋₈cycloalkanyl;C₃₋₈cycloalkanyloxy; nitro; amino; C₁₋₈alkanylamino; C₁₋₈dialkanylamino;C₃₋₈cycloalkanylamino; cyano; carboxy; C₁₋₇alkanyloxycarbonyl;C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl; phenyl optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxyl, nitro, amino and cyano; aroyl;carbamoyl; amidino; (C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl; n is an integer from 1 to 3; m is an integerfrom 0 to 3; R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino; Lis a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl, orC₃₋₈cycloalkandiyl; R₃ is selected from the group consisting of phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₈alkanyl, halogen,C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; and heteroaryl optionally substituted withone to three substituents independently selected from the groupconsisting of C₁₋₈alkanyl, halogen, nitro, amino and cyano wherein saidheteroaryl is quinolinyl, quinolinyl-N-oxide, isoquinolinyl,isoquinolinyl-N-oxide, pyridyl, pyridyl-N-oxide, pyrimidyl, furyl,thienyl or imidazolyl; R₄ is selected from the group consisting ofhydrogen and C₁₋₈alkanyl; R₅ is hydrogen; X is selected from the groupconsisting of O and S; and enantiomers, diastereomers, tautomers,solvates, and pharmaceutically acceptable salts thereof.
 79. Thecomposition of claim 78 wherein R₁ is a substituent independentlyselected from the group consisting of hydrogen; hydroxy; fluoro; chloro;and C₁₋₈alkanyloxy.
 80. The composition of claim 78 wherein R₁ is asubstituent independently selected from the group consisting of fluoro;chloro; and C₁₋₈alkanyloxy.
 81. The composition of claim 78 wherein R₂is independently selected from the group consisting of hydrogen;C₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl; C₃₋₈cycloalkanyl; phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of fluoro, chloro, bromo, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, and fluorinatedalkanyl; naphthyl optionally substituted with one to three substituentsindependently selected from the group consisting of fluoro, chloro,bromo, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, andfluorinated alkanyl; and a heteroaryl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl, pyrimidyl,furyl, thienyl or imidazolyl.
 82. The composition of claim 78 wherein Lis a direct bond or C₁₋₈alkandiyl.
 83. The composition of claim 78wherein R₃ is selected from the group consisting of naphthyl substitutedwith hydroxyl; quinolinyl optionally substituted with one or moresubstituents selected from the group consisting of methyl and chloro;quinolinyl-N-oxide; isoquinolinyl optionally substituted with one ormore substituents selected from the group consisting of methyl andchloro and isoquinolinyl-N-oxide.
 84. A composition comprising acompound of Formula (I):

wherein: R₁ is a substituent independently selected from the groupconsisting of hydrogen; hydroxy; halogen; C₁₋₈alkanyl optionallyindependently substituted with one or more substituents independentlyselected from the group consisting of halogen, fluorinated alkanyl andC₁₋₈alkanyloxy; C₁₋₈alkanyloxy optionally independently substituted withone or more substituents independently selected from the groupconsisting of halogen, fluorinatedalkanyl and C₁₋₈alkanyloxy;fluorinated alkanyloxy; fluorinated alkanyl; C₁₋₈alkanylthio optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, fluorinated alkanyl and C₁₋₈alkanyloxy;C₃₋₈cycloalkanyl; C₃₋₈cycloalkanyloxy; nitro; amino; C₁₋₈alkanylamino; C₁₈dialkanylamino; C₃₋₈cycloalkanylamino; cyano; carboxy;C₁₋₇alkanyloxycarbonyl; C₁₋₇alkanylcarbonyloxy; formyl; carbamoyl;phenyl optionally substituted with one to three substituentsindependently selected from the group consisting of halogen, hydroxyl,nitro, amino and cyano; aroyl; carbamoyl; amidino;(C₁₋₈alkanylamino)carbonyl; (arylamino)carbonyl andaryl(C₁₋₈alkanyl)carbonyl; n is an integer from 1 to 3; m is an integerfrom 0 to 3; R₂ is independently selected from the group consisting ofhydrogen; hydroxy; C₁₋₈alkanyl; C₂₋₈alkenyl; C₁₋₈alkylidenyl;C₁₋₈alkylidynyl; fluoro; chloro; C₃₋₈cycloalkanyl; phenyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy,phenyl(C₁₋₈)alkanyloxy, fluorinated alkanyl, cyano, nitro, amino,C₁₋₈alkanylamino, and C₁₋₈dialkanylamino; phenoxy optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, fluorinatedalkanyl, cyano and nitro; and heteroaryl optionally substituted with oneto three substituents independently selected from the group consistingof C₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl,pyrimidyl, furyl, thienyl or imidazolyl; pyrrolidino; and piperidino; Lis a direct bond, C₁₋₈alkandiyl, C₂₋₈alkendiyl, C₂₋₈alkyndiyl, orC₃₋₈cycloalkandiyl; R₃ is selected from the group consisting of phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of C₁₋₈alkanyl, halogen,C₁₋₈alkanyloxy, hydroxy, fluorinated alkanyl, nitro, amino,di(C₁₋₈)alkanylamino, C₁₋₈alkanylamino and cyano; naphthyl optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₈alkanyl, halogen, C₁₋₈alkanyloxy, hydroxy,fluorinated alkanyl, nitro, amino, di(C₁₋₈)alkanylamino,C₁₋₈alkanylamino and cyano; and heteroaryl optionally substituted withone to three substituents independently selected from the groupconsisting of C₁₋₈alkanyl, halogen, nitro, amino and cyano wherein saidheteroaryl is quinolinyl, quinolinyl-N-oxide, isoquinolinyl,isoquinolinyl-N-oxide, pyridyl, pyridyl-N-oxide, pyrimidyl, furyl,thienyl or imidazolyl; R₄ is selected from the group consisting ofhydrogen and C₁₋₈alkanyl; R₅ is selected from the group consisting ofhydrogen and C₁₋₈alkanyl; X is O; and enantiomers, diastereomers,tautomers, solvates, and pharmaceutically acceptable salts thereof. 85.The composition of claim 84 wherein R₁ is a substituent independentlyselected from the group consisting of hydrogen; hydroxy; fluoro; chloro;and C₁₋₈alkanyloxy.
 86. The composition of claim 84 wherein R₁ is asubstituent independently selected from the group consisting of fluoro;chloro; and C₁₋₈alkanyloxy.
 87. The composition of claim 84 wherein R₂is independently selected from the group consisting of hydrogen;C₂₋₈alkenyl; C₁₋₈alkylidenyl; C₁₋₈alkylidynyl; C₃₋₈cycloalkanyl; phenyloptionally substituted with one to three substituents independentlyselected from the group consisting of fluoro, chloro, bromo, hydroxy,C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, and fluorinatedalkanyl; naphthyl optionally substituted with one to three substituentsindependently selected from the group consisting of fluoro, chloro,bromo, hydroxy, C₁₋₈alkanyl, C₁₋₈alkanyloxy, phenyl(C₁₋₈)alkanyloxy, andfluorinated alkanyl; and a heteroaryl optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₆alkanyl and halogen wherein said heteroaryl is pyridyl, pyrimidyl,furyl, thienyl or imidazolyl.
 88. The composition of claim 84 wherein Lis a direct bond or C₁₋₈alkandiyl.
 89. The composition of claim 84wherein R₃ is selected from the group consisting of naphthyl substitutedwith hydroxyl; quinolinyl optionally substituted with one or moresubstituents selected from the group consisting of methyl and chloro;quinolinyl-N-oxide; isoquinolinyl optionally substituted with one ormore substituents selected from the group consisting of methyl andchloro and isoquinolinyl-N-oxide.
 90. A composition comprising acompound of Formula (Ia):

said compound selected from the group consitisting of a compound offormula (Ia) wherein R₁ is 6-F, R₂ is 3-Pyridinyl, m is 1, L is —CH₂—,R₃ is (3-OMe-4-OH)Ph, and X is S; a compound of formula (Ia) wherein R₁is 6-OMe, R₂ is H, m is 0, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1, L is—CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S; a compound of formula (Ia)wherein R₁ is H, R₂ is 3-Pyridinyl, m is 1, L is —CH₂—, R₃ is(3-OMe-4-(Methoxymethyleneoxy)Ph, and X is S; a compound of formula (Ia)wherein R₁ is H, R₂ is 3-Pyridinyl, m is 1, L is —CH₂—, R₃ is(3-OMe-4-OH)Ph, and X is S; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is 3-Pyridinyl, m is 1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, andX is S; a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is —CH═CH₂ mis 1, L is —CH₂—, R₃ is (3-OMe-4-(Methoxymethyleneoxy)Ph, and X is S; acompound of formula (Ia) wherein R₁ is 6-OMe, R₂ is 4-Imidazolyl, m is1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S; a compound of formula(Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂—, R₃ is(3,4-methylenedioxy)Ph, and X is O; a compound of formula (Ia) whereinR₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂—, R₃ is (3,4-diOMe)Ph, and X isO; a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is (4-tBu)Ph, and X is O; a compound of formula (Ia)wherein R₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂CH₂—, R₃ is (4-Cl)Ph,and X is O; a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, mis 1, L is —CH₂CH₂—, R₃ is (3,4-diOMe)Ph, and X is O; a compound offormula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂—, R₃ is(3,4-methylenedioxy)Ph, and X is S; a compound of formula (Ia) whereinR₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂—, R₃ is (3,4-diOMe)Ph, and X isS; a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is (4-tBu)Ph, and X is S; a compound of formula (Ia)wherein R₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂CH₂—, R₃ is (4-Cl)Ph,and X is S; a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, mis 1, L is —CH₂CH₂—, R₃ is (3,4-diOMe)Ph, and X is S; a compound offormula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂—, R₃ is(3-OMe-4-OH)Ph, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is Ph, m is 1, L is —CH═CH—( ), R₃ is (3-OMe-4-OH)Ph, and X isO; a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, L is—CH₂—, R₃ is (3-OMe-4-(Methoxymethyleneoxy)Ph, and X is S; a compound offormula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, L is —CH₂—, R₃ is(3-OMe-4-OH)Ph, and X is S; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is Ph, m is 1, L is —CH₂—, R₃ is (4-N(Me)(C₅H₁₁))Ph, and X isO; a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is (4-[N(Me)(cyclohexyl)])Ph, and X is O; a compound offormula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, L is —CH₂—, R₃ is(3,4-diOMe)Ph, and X is S; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is Ph, m is 1, L is —CH₂—, R₃ is (4-CF₃)Ph, and X is O; acompound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1, L is—CH₂—, R₃ is (3,4-diCl)Ph, and X is O; a compound of formula (Ia)wherein R₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂CH₂—, R₃ is(3,4-diCl)Ph, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is Ph, m is 1, L is —CH₂—, R₃ is (4-CF₃)Ph, and X is S; acompound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1, L is—CH₂—, R₃ is (3,4-diCl)Ph, and X is S; a compound of formula (Ia)wherein R₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂CH₂—, R₃ is(3,4-diCl)Ph, and X is S; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, andX is O; a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is1, L is a direct bond, R₃ is 3-quinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1, L is a direct bond,R₃ is 8-(2-naphtholyl), and X is O; a compound of formula (Ia) whereinR₁ is H, R₂ is H, m is 0, L is a direct bond, R₃ is 5-isoquinolinyl, andX is O; a compound of formula (Ia) wherein R₁ is 6-F, R₂ is H, m is 0, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃is 5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-Br, R₂ is Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and Xis O; a compound of formula (Ia) wherein R₁ is 6,7-diOMe, R₂ is Ph, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is 7-C1, R₂ is Ph, m is 1, L is a direct bond,R₃ is 5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁is 5-C1, R₂ is Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl,and X is O; a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is 6-OMe, R₂ is (3-Cl)Ph, m is 1, L is a directbond, R₃ is 5-isoquinolinyl, and X is O; a compound of formula (Ia)wherein R₁ is 6-OMe, R₂ is 3-Pyridinyl, m is 1, L is a direct bond, R₃is 5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is (3-Cl)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is 3-Pyridinyl, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6,7-diOMe, R₂ is Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl,and X is O; a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is(2-Cl)Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-Cl)Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is 6-OMe, R₂ is H, m is 0, L is a direct bond,R₃ is 5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁is 6-OMe, R₂ is (2-Cl)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is (2-CF₃)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is (3-CF₃)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is (4-CF₃)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OH, R₂ is Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and Xis O; a compound of formula (Ia) wherein R₁ is H, R₂ is —CH═CH₂, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is 6-Br, R₂ is H, m is 0, L is a direct bond, R₃is 5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-C1, R₂ is H, m is 0, L is a direct bond, R₃ is 5-isoquinolinyl, and Xis O; a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is 5-isoquinolinyl, and X is O; a compound of formula (Ia)wherein R₁ is 7-C1, R₂ is H, m is 0, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is8-C1, R₂ is Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and Xis O; a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-CN)Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compoundof formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-Br)Ph, m is 1, L is adirect bond, R₃ is 5-isoquinolinyl, and X is O; a compound of formula(Ia) wherein R₁ is 6-C1, R₂ is CN, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6,7-diF, R₂ is Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl,and X is O; a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is1, L is a direct bond, R₃ is 8-(2-naphtholyl), and X is O; a compound offormula (Ia) wherein R₁ is 6-OMe, R₂ is —CH═CH₂, m is 1, L is a directbond, R₃ is 5-isoquinolinyl, and X is O; a compound of formula (Ia)wherein R₁ is 6-F, R₂ is —CH═CH₂, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is (4-OMe)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-F, R₂ is Cyclopropyl, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is (4-OMe)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is (2-OMe)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is (4-Benzyloxy)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is Ph, m is 1, L is —CH₂—, R₃ is 4-Pyridinyl, and X is O; acompound of formula (Ia) wherein R₁ is 6-F, R₂ is 2-Thienyl, m is 1, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is 6-OMe, R₂ is (2,6-diF)Ph, m is 1, L is adirect bond, R₃ is 5-isoquinolinyl, and X is O; a compound of formula(Ia) wherein R₁ is 6-OMe, R₂ is —CH₂═CH₂, m is 1, L is —CH₂—, R₃ is(3-OMe-4-OH)Ph, and X is S; a compound of formula (Ia) wherein R₁ is7-F, R₂ is Ph, m is 1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S; acompound of formula (Ia) wherein R₁ is 5-F, R₂ is Ph, m is 1, L is—CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S; a compound of formula (Ia)wherein R₁ is H, R₂ is Ph, m is 1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, andX is S; a compound of formula (Ia) wherein R, is H, R₂ is H, m is 1, Lis —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S; a compound of formula (Ia)wherein R₁ is 6-F, R₂ is H, m is 1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph,and X is S; a compound of formula (Ia) wherein R₁ is H, R₂ isCyclopropyl, m is 1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S; acompound of formula (Ia) wherein R₁ is H, R₂ is 3-thienyl, m is 1, L is—CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S; a compound of formula (Ia)wherein R₁ is H, R₂ is 2-thienyl, m is 1, L is —CH₂—, R₃ is(3-OMe-4-OH)Ph, and X is S; a compound of formula (Ia) wherein R₁ is H,R₂ is 3-furyl, m is 1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S; acompound of formula (Ia) wherein R₁ is H, R₂ is 2-furyl, m is 1, L is—CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S; a compound of formula (Ia)wherein R, is H, R₂ is 4-pyridinyl, m is 1, L is —CH₂—, R₃ is(3-OMe-4-OH)Ph, and X is S; a compound of formula (Ia) wherein R₁ is H,R₂ is 3-pyridinyl, m is 1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, L is—CH₂CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S; a compound of formula (Ia)wherein R₁ is H, R₂ is Ph, m is 1, L is —CH₂CH(Me)—, R₃ is(3-OMe-4-OH)Ph, and X is S; a compound of formula (Ia) wherein R₁ is H,R₂ is Ph, m is 1, L is —CH(Me)CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S; acompound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, L is—CH₂CH₂—, R₃ is (3-OMe-4-OCH₂CH₂NH₂)Ph, and X is S; a compound offormula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, L is —CH₂CH(Me)—, R₃ is(3-OMe-4-OCH₂CH₂NH₂)Ph, and X is S; a compound of formula (Ia) whereinR₁ is H, R₂ is Ph, m is 1, L is —CH(Me)CH₂—, R₃ is(3-OMe-4-OCH₂CH₂NH₂)Ph, and X is S; a compound of formula (Ia) whereinR₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂—, R₃ is 4-pyridinyl, and X isS; a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, L is—CH₂—, R₃ is 4-pyridinyl, and X is S; a compound of formula (Ia) whereinR₁ is 6-C1, R₂ is Ph, m is 1, L is —CH₂—, R₃ is 4-pyridinyl, and X is S;a compound of formula (Ia) wherein R₁ is 6,7-diF, R₂ is Ph, m is 1, L is—CH₂—, R₃ is 4-pyridinyl, and X is S; a compound of formula (Ia) whereinR₁ is 7-C1, R₂ is Ph, m is 1, L is —CH₂—, R₃ is 4-pyridinyl, and X is S;a compound of formula (Ia) wherein R₁ is 5-C1, R₂ is Ph, m is 1, L is—CH₂—, R₃ is 4-pyridinyl, and X is S; a compound of formula (Ia) whereinR₁ is 8-C1, R₂ is Ph, m is 1, L is —CH₂—, R₃ is 4-pyridinyl, and X is S;a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-OMe)Ph, m is 1,L is —CH₂—, R₃ is 4-pyridinyl, and X is S; a compound of formula (Ia)wherein R₁ is 6-OMe, R₂ is (3-OMe)Ph, m is 1, L is —CH₂—, R₃ is4-pyridinyl, and X is S; a compound of formula (Ia) wherein R₁ is 6-OMe,R₂ is (2-OMe)Ph, m is 1, L is —CH₂—, R₃ is 4-pyridinyl, and X is S; acompound of formula (Ia) wherein R₁ is 6,7-diOMe, R₂ is —CH₂═CH₂, m is1, L is —CH₂—, R₃ is 4-pyridinyl, and X is S; a compound of formula (Ia)wherein R₁ is 6-F, R₂ is cyclopropyl, m is 1, L is —CH₂—, R₃ is4-pyridinyl, and X is S; a compound of formula (Ia) wherein R₁ is6-t-Bu, R₂ is (4-t-Bu)Ph, m is 1, L is —CH₂—, R₃ is 4-pyridinyl, and Xis S; a compound of formula (Ia) wherein R₁ is 6-CF₃, R₂ is (4-CF₃)Ph, mis 1, L is —CH₂—, R₃ is 4-pyridinyl, and X is S; a compound of formula(Ia) wherein R₁ is H, R₂ is Ph, m is 1, L is —CH₂—, R₃ is 3-pyridinyl,and X is S; a compound of formula (Ia) wherein R₁ is 8-F, R₂ is Ph, m is1, L is —CH₂—, R₃ is 2-pyridinyl, and X is S; a compound of formula (Ia)wherein R₁ is H, R₂ is Ph, m is 1, L is —CH₂CH₂—, R₃ is 4-pyridinyl, andX is S; a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis —CH₂CH₂—, R₃ is 3-pyridinyl, and X is S; a compound of formula (Ia)wherein R₁ is H, R₂ is Ph, m is 1, L is —CH₂CH₂—, R₃ is 2-pyridinyl, andX is S; a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, Lis —CH₂—, R₃ is (2-OMe-3-OH)-5-thienyl, and X is S; a compound offormula (Ia) wherein R₁ is 6,7-diF, R₂ is Ph, m is 1, L is a directbond, R₃ is 5-isoquinolinyl, and X is O; a compound of formula (Ia)wherein R₁ is 8-C1, R₂ is Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is (2-OMe)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6,7-diOMe, R₂ is —CH₂═CH₂, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-t-Bu, R₂ is (4-t-Bu)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-CF₃, R₂ is (4-CF₃)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-F, R₂ is (4-Cl)Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl,and X is O; a compound of formula (Ia) wherein R₁ is 6-F, R₂ is(3-Cl)Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;a compound of formula (Ia) wherein R₁ is 6-F, R₂ is (2-Cl)Ph, m is 1, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is H, R₂ is (4-CF₃)Ph, m is 1, L is a directbond, R₃ is 5-isoquinolinyl, and X is O; a compound of formula (Ia)wherein R₁ is H, R₂ is (3-CF₃)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is H,R₂ is (2-CF₃)Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, andX is O; a compound of formula (Ia) wherein R₁ is H, R₂ is(3-OMe-4-OH)Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and Xis O; a compound of formula (Ia) wherein R₁ is H, R₂ is (3-OH-4-OMe)Ph,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O; acompound of formula (Ia) wherein R₁ is 6-OMe-7-OH, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is 6-OH-7-OMe, R₂ is Ph, m is 1, L is a directbond, R₃ is 5-isoquinolinyl, and X is O; a compound of formula (Ia)wherein R₁ is 6-Me, R₂ is Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-C(Me₂)CH₂Me, R₂ is Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-NO₂, R₂ is Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, andX is O; a compound of formula (Ia) wherein R₁ is 6-OSO₃Me, R₂ is Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compoundof formula (Ia) wherein R₁ is 6-NHSO₂Ph, R₂ is Ph, m is 1, L is a directbond, R₃ is 5-isoquinolinyl, and X is O; a compound of formula (Ia)wherein R₁ is 6-CO₂H, R₂ is Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-C(O)NH₂, R₂ is Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl,and X is O; a compound of formula (Ia) wherein R₁ is 6-C(O)NMe₂, R₂ isPh, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O; acompound of formula (Ia) wherein R₁ is 6-C(O)NHMe, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is 6-CO₂Ph, R₂ is Ph, m is 1, L is a directbond, R₃ is 5-isoquinolinyl, and X is O; a compound of formula (Ia)wherein R₁ is 6-cyclohexyl, R₂ is Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-Ph, R₂ is Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and Xis O; a compound of formula (Ia) wherein R₁ is6-NHC(O)(CH₂)₄—CH═CH—CH(Me)₂, R₂ is Ph, m is 1, L is a direct bond, R₃is 5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ isH, R₂ is 2-pyridinyl, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl,and X is O; a compound of formula (Ia) wherein R₁ is H, R₂ is3-pyridinyl, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X isO; a compound of formula (Ia) wherein R₁ is H, R₂ is 4-pyridinyl, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is H, R₂ is 3-thienyl, m is 1, L is a directbond, R₃ is 5-isoquinolinyl, and X is O; a compound of formula (Ia)wherein R₁ is H, R₂ is 3-furyl, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is H,R₂ is 2-furyl, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and Xis O; a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 3-hydroxynaphth-8-yl, and X is O; a compound offormula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃is 1-hydroxynaphth-8-yl, and X is O; a compound of formula (Ia) whereinR₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is4-hydroxynaphth-8-yl, and X is O; a compound of formula (Ia) wherein R₁is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is5-hydroxynaphth-8-yl, and X is O; a compound of formula (Ia) wherein R₁is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is3-chloro-2-hydroxynaphth-8-yl, and X is O; a compound of formula (Ia)wherein R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is2,3-dihydroxynaphth-8-yl, and X is O; a compound of formula (Ia) whereinR₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is 5-quinolinyl, andX is O; a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-cinnolinyl, and X is O; a compound offormula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃is 3-Me-5-quinolinyl, and X is O; a compound of formula (Ia) wherein R₁is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is4-(1,8-naphthyridinyl), and X is O; a compound of formula (Ia) whereinR₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is 5-quinazolinyl,and X is O; a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is1, L is a direct bond, R₃ is 2-OH-5-quinolinyl, and X is O; a compoundof formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond,R₃ is 3-OH-5-quinolinyl, and X is O; a compound of formula (Ia) whereinR₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is 3-F-5-quinolinyl,and X is O; a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is1, L is a direct bond, R₃ is 3-Cl-5-quinolinyl, and X is O; a compoundof formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond,R₃ is 2-OH-3-Cl-5-quinolinyl, and X is O; a compound of formula (Ia)wherein R₁ is 6-F, R₂ is —CH₂═CH₂ m is 1, L is a direct bond, R₃ is5-quinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is 6-F,R₂ is —CH₂CH₃, m is 1, L is a direct bond, R₃ is 5-quinolinyl, and X isO; a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, L isa direct bond, R₃ is 8-Cl-5-quinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is H, R₂ is 2-naphthyl, m is 1, L is a directbond, R₃ is 5-isoquinolinyl, and X is O; a compound of formula (Ia)wherein R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is1,3-diMe-5-isoquinolinyl, and X is O; a compound of formula (Ia) whereinR₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is8-Cl-5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is1,3-diMe-8-Cl-5-isoquinolinyl, and X is O; a compound of formula (Ia)wherein R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ isisoquinolin-N-oxide-5-yl, and X is O; a compound of formula (Ia) whereinR₁ is 6-F, R₂ is Ph, m is 1, L is —CH₂—, R₃ is 5-isoquinolinyl, and X isO; a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, L isa direct bond, R₃ is 3-quinolinyl, and X is O; a compound of formula(Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is3-quinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OH-7-OMe, R₂ is Ph, m is 1, L is a direct bond, R₃ is 3-quinolinyl,and X is O; a compound of formula (Ia) wherein R₁ is 6,7-diOH, R₂ is Ph,m is 1, L is a direct bond, R₃ is 3-quinolinyl, and X is O; a compoundof formula (Ia) wherein R₁ is 6-OMe-7-OH, R₂ is Ph, m is 1, L is adirect bond, R₃ is 3-quinolinyl, and X is O; a compound of formula (Ia)wherein R₁ is H, R₂ is Ph, m is 1, L is a direct bond, R₃ is3-quinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is 6-F,R₂ is Ph, m is 1, L is a direct bond, R₃ is 1-Cl-5-isoquinolinyl, and Xis O; a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 1-Me-5-isoquinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃is 3-Me-5-isoquinolinyl, and X is O; a compound of formula (Ia) whereinR₁ is 6-Br, R₂ is Ph, m is 1, L is a direct bond, R₃ is 8-isoquinolinyl,and X is O; a compound of formula (Ia) wherein R₁ is 6-F, R₂ is 2-furyl,m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O; acompound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1, L is adirect bond, R₃ is 5-isoquinolinyl, and X is O; a compound of formula(Ia) wherein R₁ is 6-F, R₂ is 3-furanyl, m is 1, L is a direct bond, R₃is 5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R, is6-OCH₃, R₂ is 3-thienyl, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O a compound of formula (Ia) wherein R₁ is6-OCH₃, R₂ is 2,4 di-F Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OCH₃, R₂ is 2,4 di-F Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OCH₃, R₂ is Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, andX is O; a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compound offormula (Ia) wherein R, is 6-C1, R₂ is Ph, m is 1, L is a direct bond,R₃ is 5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl-N-oxide, and X is O; a compound of formula (Ia) whereinR₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is4-Cl-5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is4-Cl-5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is3-methyl-5-isoquinolinyl, and X is O; a compound of formula (Ia) whereinR₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is1-methyl-5-isoquinolinyl, and X is O; a compound of formula (Ia) whereinR₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is1-Cl-5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R,is 6-C₁, R₂ is Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl-N-oxide, and X is O; a compound of formula (Ia) whereinR₁ is 6-F, R₂ is 4-CF₃ Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is1,3-diCl-5-isoquinolinyl, and X is O; a compound of formula (Ia) whereinR₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is1,3-diCl-5-isoquinolinyl, and X is O; a compound of formula (Ia) whereinR₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is8-Cl-5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is1-piperidinyl-5-isoquinolinyl, and X is O; a compound of formula (Ia)wherein R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is1-OCH₃-5-isoquinolinyl, and X is O; a compound of formula (Ia) whereinR₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is1-F-5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is1-N,N-dimethyl-5-isoquinolinyl, and X is O; a compound of formula (Ia)wherein R₁ is 6-C1, R₂ is nil, m is nil, R₃ is 1-CH₃-5-isoquinolinyl,and X is O; a compound of formula (Ia) wherein R₁ is 6-C1, R₂ is nil, mis nil, R₃ is 1-Cl-5-isoquinolinyl, and X is O; a compound of formula(Ia) wherein R₁ is 6-F, R₂ is 3-CF₃ Ph, m is 1, L is a direct bond, R₃is 5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-F, R₂ is 3-CF₃ Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl-N-oxide, and X is O; a compound of formula (Ia) whereinR₁ is 6-F, R₂ is 3-CF₃ Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl-N-oxide, and X is O; a compound of formula (Ia) whereinR₁ is 6-F, R₂ is spiro-2-indanyl, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-F, R₂ is 4-Cl, 3-CF₃ Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; and a compound of formula (Ia) wherein R₁is 6-C1, R₂ is Ph, m is 1, L is a direct bond, R₃ is1-CH₃-5-isoquinolinyl, and X is O; enantiomers, diastereomers,tautomers, solvates, and pharmaceutically acceptable salts thereof. 91.A composition comprising a compound of Formula (Ia):

said compound selected from the group consitisting of a compound offormula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂—, R₃ is(3-OMe-4-OH)Ph, and X is S; a compound of formula (Ia) wherein R₁ is H,R₂ is 3-Pyridinyl, m is 1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is S;a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1, L is—CH₂—, R₃ is (3-OMe-4-OH)Ph, and X is O; a compound of formula (Ia)wherein R₁ is H, R₂ is Ph, m is 1, L is —CH₂—, R₃ is (3-OMe-4-OH)Ph, andX is S; a compound of formula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1,L is —CH₂—, R₃ is (3,4-diOMe)Ph, and X is S; a compound of formula (Ia)wherein R₁ is 6-OMe, R₂ is Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is Ph, m is 1, L is a direct bond, R₃ is 8-(2-naphtholyl), andX is O; a compound of formula (Ia) wherein R₁ is H, R₂ is H, m is 0, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is 6-F, R₂ is H, m is 0, L is a direct bond, R₃is 5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and Xis O; a compound of formula (Ia) wherein R₁ is 6-Br, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is 6,7-diOMe, R₂ is Ph, m is 1, L is a directbond, R₃ is 5-isoquinolinyl, and X is O; a compound of formula (Ia)wherein R₁ is 7-C1, R₂ is Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is5-C₁, R₂ is Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and Xis O; a compound of formula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, L isa direct bond, R₃ is 5-isoquinolinyl, and X is O; a compound of formula(Ia) wherein R₁ is 6-OMe, R₂ is (3-Cl)Ph, m is 1, L is a direct bond, R₃is 5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6,7-diOMe, R₂ is Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl,and X is O; a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is(2-Cl)Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-Cl)Ph, m is 1,L is a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is 6-OMe, R₂ is H, m is 0, L is a direct bond,R₃ is 5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁is 6-OMe, R₂ is (2-CF₃)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is (3-CF₃)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is (4-CF₃)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is H,R₂ is —CH═CH₂, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and Xis O; a compound of formula (Ia) wherein R₁ is 6-Br, R₂ is H, m is 0, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is 6-C1, R₂ is H, m is 0, L is a direct bond, R₃is 5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-F, R₂ is Ph, m is 1, L is —CH₂—, R₃ is 5-isoquinolinyl, and X is O; acompound of formula (Ia) wherein R₁ is 7-C1, R₂ is H, m is 0, L is adirect bond, R₃ is 5-isoquinolinyl, and X is O; a compound of formula(Ia) wherein R₁ is 8-C1, R₂ is Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is (4-CN)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is (4-Br)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6,7-diF, R₂ is Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl,and X is O; a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is—CH═CH₂, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;a compound of formula (Ia) wherein R₁ is 6-F, R₂ is —CH═CH₂, m is 1, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is 6-OMe, R₂ is (4-OMe)Ph, m is 1, L is a directbond, R₃ is 5-isoquinolinyl, and X is O; a compound of formula (Ia)wherein R₁ is 6-OMe, R₂ is (2-OMe)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-F, R₂ is 2-Thienyl, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl,and X is O; and enantiomers, diastereomers, tautomers, solvates, andpharmaceutically acceptable salts thereof.
 92. A composition comprisinga compound of Formula (Ia):

said compound selected from the group consitisting of a compound offormula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, L is a direct bond, R₃is 5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-Br, R₂ is Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and Xis O; a compound of formula (Ia) wherein R₁ is 5-C1, R₂ is Ph, m is 1, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is H, R₂ is Ph, m is 1, L is a direct bond, R₃is 5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-Br, R₂ is H, m is 0, L is a direct bond, R₃ is 5-isoquinolinyl, and Xis O; a compound of formula (Ia) wherein R₁ is 6-C1, R₂ is H, m is 0, Lis a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is 6-F, R₂ is Ph, m is 1, L is —CH₂—, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is7-C1, R₂ is H, m is 0, L is a direct bond, R₃ is 5-isoquinolinyl, and Xis O; a compound of formula (Ia) wherein R₁ is 6,7-diF, R₂ is Ph, m is1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O; a compound offormula (Ia) wherein R₁ is 6-F, R₂ is —CH═CH₂, m is 1, L is a directbond, R₃ is 5-isoquinolinyl, and X is O; a compound of formula (Ia)wherein R₁ is 6-F, R₂ is 2-Thienyl, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O.
 93. A composition comprising a compound ofFormula (Ia):

said compound selected from the group consitisting of a compound offormula (Ia) wherein R₁ is 6-OMe, R₂ is Ph, m is 1, L is —CH₂—, R₃ is(3-OMe-4-OH)Ph, and X is S; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is (3-Cl)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is (2-Cl)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is (2-CF₃)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is (3-CF₃)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-OMe, R₂ is (4-CF₃)Ph, m is 1, L is a direct bond, R₃ is5-isoquinolinyl, and X is O; a compound of formula (Ia) wherein R₁ is6-F, R₂ is Ph, m is 1, L is a direct bond, R₃ is 3-Me-5-isoquinolinyl,and X is O; a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is(4-Br)Ph, m is 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O;and a compound of formula (Ia) wherein R₁ is 6-OMe, R₂ is (4-OMe)Ph, mis 1, L is a direct bond, R₃ is 5-isoquinolinyl, and X is O.
 94. Apharmaceutical composition comprising a compound, salt or solvateaccording to claim 1 admixed with a pharmaceutically acceptable carrier,excipient or diluent.
 95. A veterinary composition comprising acompound, salt or solvate according to claim 1 admixed with aveterinarily acceptable carrier, excipient or dilluent.
 96. A method oftreating or preventing a disease or condition in a mammal which diseaseor condition is affected by the modulation of one or more vanilloidreceptors, which method comprises administering to a mammal in need ofsuch treatment or prevention a therapeutically effective amount of acompound, salt or solvate of claim
 1. 97. A method for preventing ortreating a chronic-pain causing disease or condition, an acute-paincausing disease or condition, or a pulmonary dysfunction comprising thestep of administering to a mammal in need of such treatment atherapeutically effective amount of a compound, salt or solvate ofclaim
 1. 98. A method for preventing or treating a disease or condition,wherein said disease or condition causes inflammatory pain, burningpain, itch urinary incontinence, or chronic obstructive pulmonarydisease, said method comprising the step of administering to a mammal inneed of such treatment a therapeutically effective amount of a compound,salt or solvate of claim
 1. 99. A method for preventing or treating adisease or condition selected from the group consisting ofosteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache,toothache, burn, sunburn, snake bite (in particular, venomous snakebite), spider bite, insect sting, neurogenic bladder, benign prostatichypertrophy, interstitial cystitis, urinary tract infection, cough,asthma, chronic obstructive pulmonary disease, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, anxiety, panic disorders,inflammatory bowel diseases, pharyngitis, mucositis, enteritis,cellulites, peripheral neuropathy, bilateral peripheral neuropathy,diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia,causalgia, sciatic neuritis, mandibular joint neuralgia, peripheralneuritis, polyneuritis, stump pain, phantom limb pain, bony fractures,post-operative ileus, irritable bowel syndrome, Crohn's Disease,ulcerative colitis, cholecystitis, pancreatitis, postmastectomy painsyndrome, oral neuropathic pain, Charcot's pain, reflex sympatheticdystrophy, Guillain-Barre syndrome, meralgia paresthetica, burning-mouthsyndrome, optic neuritis, postfebrile neuritis, migrating neuritis,segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachialneuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngialneuralgia, migrainous neuralgia, idiopathic neuralgia, intercostalsneuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia,occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatineneuralgia, supraorbital neuralgia, vidian neuralgia, sinus headache,tension headache, labor, childbirth, intestinal gas, menstrual cramps,cancer, and trauma, said method comprising the step of administering toa mammal in need of such treatment a therapeutically effective amount ofa compound, salt or solvate of claim
 1. 100. The method of claim 97wherein said therapeutically effective amount comprises a dose range offrom about 0.001 mg to about 1,000 mg.
 101. The method of claim 97wherein said therapeutically effective amount comprises a dose range offrom about 0.1 mg to about 500 mg.
 102. The method of claim 97 whereinsaid therapeutically effective amount comprises a dose range of fromabout 1 mg to about 250 mg.
 103. A kit comprising in one or morecontainers an amount of the composition of claim 1 effective to treat orprevent a disease or condition selected from the group consisting ofosteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache,toothache, burn, sunburn, snake bite (in particular, venomous snakebite), spider bite, insect sting, neurogenic bladder, benign prostatichypertrophy, interstitial cystitis, urinary tract infection, cough,asthma, chronic obstructive pulmonary disease, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, anxiety, panic disorders,inflammatory bowel diseases, pharyngitis, mucositis, enteritis,cellulites, peripheral neuropathy, bilateral peripheral neuropathy,diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia,causalgia, sciatic neuritis, mandibular joint neuralgia, peripheralneuritis, polyneuritis, stump pain, phantom limb pain, bony fractures,post-operative ileus, irritable bowel syndrome, Crohn's Disease,ulcerative colitis, cholecystitis, pancreatitis, postmastectomy painsyndrome, oral neuropathic pain, Charcot's pain, reflex sympatheticdystrophy, Guillain-Barre syndrome, meralgia paresthetica, burning-mouthsyndrome, optic neuritis, postfebrile neuritis, migrating neuritis,segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachialneuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngialneuralgia, migrainous neuralgia, idiopathic neuralgia, intercostalsneuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia,occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatineneuralgia, supraorbital neuralgia, vidian neuralgia, sinus headache,tension headache, labor, childbirth, intestinal gas, menstrual cramps,cancer, and trauma.
 104. A pharmaceutical composition comprising acompound, salt or solvate according to claim 90 admixed with apharmaceutically acceptable carrier, excipient or diluent.
 105. Aveterinary composition comprising a compound, salt or solvate accordingto claim 90 admixed with a veterinarily acceptable carrier, excipient ordilluent.
 106. A method for preventing or treating a disease orcondition selected from the group consisting of osteoarthritis,rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burn,sunburn, snake bite (in particular, venomous snake bite), spider bite,insect sting, neurogenic bladder, benign prostatic hypertrophy,interstitial cystitis, urinary tract infection, cough, asthma, chronicobstructive pulmonary disease, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, anxiety, panic disorders,inflammatory bowel diseases, pharyngitis, mucositis, enteritis,cellulites, peripheral neuropathy, bilateral peripheral neuropathy,diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia,causalgia, sciatic neuritis, mandibular joint neuralgia, peripheralneuritis, polyneuritis, stump pain, phantom limb pain, bony fractures,post-operative ileus, irritable bowel syndrome, Crohn's Disease,ulcerative colitis, cholecystitis, pancreatitis, postmastectomy painsyndrome, oral neuropathic pain, Charcot's pain, reflex sympatheticdystrophy, Guillain-Barre syndrome, meralgia paresthetica, burning-mouthsyndrome, optic neuritis, postfebrile neuritis, migrating neuritis,segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachialneuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngialneuralgia, migrainous neuralgia, idiopathic neuralgia, intercostalsneuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia,occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatineneuralgia, supraorbital neuralgia, vidian neuralgia, sinus headache,tension headache, labor, childbirth, intestinal gas, menstrual cramps,cancer, and trauma, said method comprising the step of administering toa mammal in need of such treatment a therapeutically effective amount ofa compound, salt or solvate of claim
 90. 107. The method of claim 104wherein said therapeutically effective amount comprises a dose range offrom about 0.001 mg to about 1,000 mg.
 108. The method of claim 104wherein said therapeutically effective amount comprises a dose range offrom about 0.1 mg to about 500 mg.
 109. The method of claim 104 whereinsaid therapeutically effective amount comprises a dose range of fromabout 1 mg to about 250 mg.
 110. A kit comprising in one or morecontainers an amount of the composition of claim 90 effective to treator prevent a disease or condition selected from the group consisting ofosteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache,toothache, burn, sunburn, snake bite (in particular, venomous snakebite), spider bite, insect sting, neurogenic bladder, benign prostatichypertrophy, interstitial cystitis, urinary tract infection, cough,asthma, chronic obstructive pulmonary disease, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, anxiety, panic disorders,inflammatory bowel diseases, pharyngitis, mucositis, enteritis,cellulites, peripheral neuropathy, bilateral peripheral neuropathy,diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia,causalgia, sciatic neuritis, mandibular joint neuralgia, peripheralneuritis, polyneuritis, stump pain, phantom limb pain, bony fractures,post-operative ileus, irritable bowel syndrome, Crohn's Disease,ulcerative colitis, cholecystitis, pancreatitis, postmastectomy painsyndrome, oral neuropathic pain, Charcot's pain, reflex sympatheticdystrophy, Guillain-Barre syndrome, meralgia paresthetica, burning-mouthsyndrome, optic neuritis, postfebrile neuritis, migrating neuritis,segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachialneuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngialneuralgia, migrainous neuralgia, idiopathic neuralgia, intercostalsneuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia,occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatineneuralgia, supraorbital neuralgia, vidian neuralgia, sinus headache,tension headache, labor, childbirth, intestinal gas, menstrual cramps,cancer, and trauma.
 111. A pharmaceutical composition comprising acompound, salt or solvate according to claim 91 admixed with apharmaceutically acceptable carrier, excipient or diluent.
 112. Aveterinary composition comprising a compound, salt or solvate accordingto claim 91 admixed with a veterinarily acceptable carrier, excipient ordilluent.
 113. A method for preventing or treating a disease orcondition selected from the group consisting of osteoarthritis,rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burn,sunburn, snake bite (in particular, venomous snake bite), spider bite,insect sting, neurogenic bladder, benign prostatic hypertrophy,interstitial cystitis, urinary tract infection, cough, asthma, chronicobstructive pulmonary disease, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, anxiety, panic disorders,inflammatory bowel diseases, pharyngitis, mucositis, enteritis,cellulites, peripheral neuropathy, bilateral peripheral neuropathy,diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia,causalgia, sciatic neuritis, mandibular joint neuralgia, peripheralneuritis, polyneuritis, stump pain, phantom limb pain, bony fractures,post-operative ileus, irritable bowel syndrome, Crohn's Disease,ulcerative colitis, cholecystitis, pancreatitis, postmastectomy painsyndrome, oral neuropathic pain, Charcot's pain, reflex sympatheticdystrophy, Guillain-Barre syndrome, meralgia paresthetica, burning-mouthsyndrome, optic neuritis, posffebrile neuritis, migrating neuritis,segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachialneuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngialneuralgia, migrainous neuralgia, idiopathic neuralgia, intercostalsneuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia,occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatineneuralgia, supraorbital neuralgia, vidian neuralgia, sinus headache,tension headache, labor, childbirth, intestinal gas, menstrual cramps,cancer, and trauma, said method comprising the step of administering toa mammal in need of such treatment a therapeutically effective amount ofa compound, salt or solvate of claim
 91. 114. The method of claim 111wherein said therapeutically effective amount comprises a dose range offrom about 0.001 mg to about 1,000 mg.
 115. The method of claim 111wherein said therapeutically effective amount comprises a dose range offrom about 0.1 mg to about 500 mg.
 116. The method of claim 111 whereinsaid therapeutically effective amount comprises a dose range of fromabout 1 mg to about 250 mg.
 117. A kit comprising in one or morecontainers an amount of the composition of claim 91 effective to treator prevent a disease or condition selected from the group consisting ofosteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache,toothache, burn, sunburn, snake bite (in particular, venomous snakebite), spider bite, insect sting, neurogenic bladder, benign prostatichypertrophy, interstitial cystitis, urinary tract infection, cough,asthma, chronic obstructive pulmonary disease, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, anxiety, panic disorders,inflammatory bowel diseases, pharyngitis, mucositis, enteritis,cellulites, peripheral neuropathy, bilateral peripheral neuropathy,diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia,causalgia, sciatic neuritis, mandibular joint neuralgia, peripheralneuritis, polyneuritis, stump pain, phantom limb pain, bony fractures,post-operative ileus, irritable bowel syndrome, Crohn's Disease,ulcerative colitis, cholecystitis, pancreatitis, postmastectomy painsyndrome, oral neuropathic pain, Charcot's pain, reflex sympatheticdystrophy, Guillain-Barre syndrome, meralgia paresthetica, burning-mouthsyndrome, optic neuritis, postfebrile neuritis, migrating neuritis,segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachialneuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngialneuralgia, migrainous neuralgia, idiopathic neuralgia, intercostalsneuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia,occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatineneuralgia, supraorbital neuralgia, vidian neuralgia, sinus headache,tension headache, labor, childbirth, intestinal gas, menstrual cramps,cancer, and trauma.